Immunology_Janeway

Immunology_Janeway. Melchers, F., ten Boekel, E., Seidl, T., Kong, X.C., Yamagami, T., Onishi, K., Shimizu, T., Rolink, A.G., and Andersson, J.: Repertoire selection by pre-B-cell receptors and B-cell receptors, and genetic control of B-cell development from immature to mature B cells. Immunol. Rev. 2000, 175:33–46. Starr, T.K., Jameson, S.C., and Hogquist, K.A.: Positive and negative selection of T cells. Annu. Rev. Immunol. 2003, 21:139–176. von Boehmer, H.: The developmental biology of T lymphocytes. Annu. Rev. Immunol. 1993, 6:309–326. Weinberg, R.A.: The Biology of Cancer, 2nd ed. New York: Garland Science, 2014. Section references. 8-1 Lymphocytes derive from hematopoietic stem cells in the bone marrow. Busslinger, M.: Transcriptional control of early B cell development. Annu. Rev. Immunol. 2004, 22:55–79. Chao, M.P., Seita, J., and Weissman, I.L.: Establishment of a normal hematopoietic and leukemia stem cell hierarchy. Cold Spring Harb. Symp. Quant. Biol. 2008, 73:439–449.


Immunology_Janeway

Immunology_Janeway. Chao, M.P., Seita, J., and Weissman, I.L.: Establishment of a normal hematopoietic and leukemia stem cell hierarchy. Cold Spring Harb. Symp. Quant. Biol. 2008, 73:439–449. Funk, P.E., Kincade, P.W., and Witte, P.L.: Native associations of early hematopoietic stem-cells and stromal cells isolated in bone-marrow cell aggregates. Blood 1994, 83:361–369. Jacobsen, K., Kravitz, J., Kincade, P.W., and Osmond, D.G.: Adhesion receptors on bone-marrow stromal cells—in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and γ-irradiated mice. Blood 1996, 87:73–82. 8.14 Multiple Choice: Which of the following would not lead to a defect in CD8+ T-cell development in the thymus? A. Genetic deletion of cathepsin. B. An inactivating mutation in the gene for the transcription factor Runx3. C. Overexpression of the transcription factor ThPOK. D. Genetic deletion of MHC class I genes. E. Genetic deletion of the proteasomal subunit β5T.


Immunology_Janeway

Immunology_Janeway. C. Overexpression of the transcription factor ThPOK. D. Genetic deletion of MHC class I genes. E. Genetic deletion of the proteasomal subunit β5T. 8.15 Multiple Choice: Which of the following best explains MHC restriction of mature T cells? A. TCRα and TCRβ CDR1 and CDR2 regions exhibit a germline-encoded bias to recognize MHC. B. Apoptosis is induced in thymocytes when they receive a strong T-cell receptor signal. C. CD4 and CD8 bind up all almost all of intracellular Lck. D. Medullary thymic epithelial cells express AIRE, which promotes the expression of tissue-specific proteins. E. Bone marrow-derived dendritic cells and macrophages are much more effective at mediating negative selection of thymocytes than thymic epithelial cells and thymocytes themselves. 8.16 Short Answer: What is the affinity hypothesis for thymocyte development? Kiel, M.J., and Morrison, S.J.: Uncertainty in the niches that maintain haematopoietic stem cells. Nat. Rev. Immunol. 2008, 8:290–301.


Immunology_Janeway

Immunology_Janeway. Kiel, M.J., and Morrison, S.J.: Uncertainty in the niches that maintain haematopoietic stem cells. Nat. Rev. Immunol. 2008, 8:290–301. 8-2 B-cell development begins by rearrangement of the heavy-chain locus. Allman, D., Li, J., and Hardy, R.R.: Commitment to the B lymphoid lineage occurs before DH-JH recombination. J. Exp. Med. 1999, 189:735–740. Allman, D., Lindsley, R.C., DeMuth, W., Rudd, K., Shinton, S.A., and Hardy, R.R.: Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation. J. Immunol. 2001, 167:6834–6840. Hardy, R.R., Carmack, C.E., Shinton, S.A., Kemp, J.D., and Hayakawa, K.: Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 1991, 173:1213–1225. Osmond, D.G., Rolink, A., and Melchers, F.: Murine B lymphopoiesis: towards a unified model. Immunol. Today 1998, 19:65–68.


Immunology_Janeway

Immunology_Janeway. Osmond, D.G., Rolink, A., and Melchers, F.: Murine B lymphopoiesis: towards a unified model. Immunol. Today 1998, 19:65–68. Welinder, E., Ahsberg, J., and Sigvardsson, M.: B-lymphocyte commitment: identifying the point of no return. Semin. Immunol. 2011, 23:335–340. 8-3 The pre-B-cell receptor tests for successful production of a complete heavy chain and signals for the transition from the pro-B cell to the pre-B cell stage. Bankovich, A.J., Raunser, S., Juo, Z.S., Walz, T., Davis, M.M., and Garcia, K.C.: Structural insight into pre-B cell receptor function. Science 2007, 316:291–294. Grawunder, U., Leu, T.M.J., Schatz, D.G., Werner, A., Rolink, A.G., Melchers, F., and Winkler, T.H.: Down-regulation of Rag1 and Rag2 gene expression in pre-B cells after functional immunoglobulin heavy-chain rearrangement. Immunity 1995, 3:601–608. Monroe, J.G.: ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat. Rev. Immunol. 2006, 6:283–294.


Immunology_Janeway

Immunology_Janeway. Monroe, J.G.: ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat. Rev. Immunol. 2006, 6:283–294. 8-4 Pre-B-cell receptor signaling inhibits further heavy-chain locus rearrangement and enforces allelic exclusion. Geier, J.K., and Schlissel, M.S.: Pre-BCR signals and the control of Ig gene rearrangements. Semin. Immunol. 2006, 18:31–39. Loffert, D., Ehlich, A., Muller, W., and Rajewsky, K.: Surrogate light-chain expression is required to establish immunoglobulin heavy-chain allelic exclusion during early B-cell development. Immunity 1996, 4:133–144. Melchers, F., ten Boekel, E., Yamagami, T., Andersson, J., and Rolink, A.: The roles of preB and B cell receptors in the stepwise allelic exclusion of mouse IgH and L chain gene loci. Semin. Immunol. 1999, 11:307–317. 8-5 Pre-B cells rearrange the light-chain locus and express cell-surface immunoglobulin.


Immunology_Janeway

Immunology_Janeway. 8-5 Pre-B cells rearrange the light-chain locus and express cell-surface immunoglobulin. Arakawa, H., Shimizu, T., and Takeda, S.: Reevaluation of the probabilities for productive rearrangements on the κ-loci and λ-loci. Int. Immunol. 1996, 8:91–99. Gorman, J.R., van der Stoep, N., Monroe, R., Cogne, M., Davidson, L., and Alt, F.W.: The Igk 3’ enhancer influences the ratio of Igκ versus IgλB lymphocytes. Immunity 1996, 5:241–252. Hesslein, D.G., and Schatz, D.G.: Factors and forces controlling V(D)J recombination. Adv. Immunol. 2001, 78:169–232. Kee, B.L., and Murre, C.: Transcription factor regulation of B lineage commitment. Curr. Opin. Immunol. 2001, 13:180–185. Sleckman, B.P., Gorman, J.R., and Alt, F.W.: Accessibility control of antigen receptor variable region gene assembly—role of cis-acting elements. Annu. Rev. Immunol. 1996, 14:459–481. Takeda, S., Sonoda, E., and Arakawa, H.: The κ–λ ratio of immature B cells. Immunol. Today 1996, 17:200–201.


Immunology_Janeway

Immunology_Janeway. Takeda, S., Sonoda, E., and Arakawa, H.: The κ–λ ratio of immature B cells. Immunol. Today 1996, 17:200–201. 8-6 Immature B cells are tested for autoreactivity before they leave the bone marrow. Casellas, R., Shih, T.A., Kleinewietfeld, M., Rakonjac, J., Nemazee, D., Rajewsky, K., and Nussenzweig, M.C.: Contribution of receptor editing to the antibody repertoire. Science 2001, 291:1541–1544. Chen, C., Nagy, Z., Radic, M.Z., Hardy, R.R., Huszar, D., Camper, S.A., and Weigert, M.: The site and stage of anti-DNA B-cell deletion. Nature 1995, 373:252–255. Cornall, R.J., Goodnow, C.C., and Cyster, J.G.: The regulation of self-reactive B cells. Curr. Opin. Immunol. 1995, 7:804–811. Melamed, D., Benschop, R.J., Cambier, J.C., and Nemazee, D.: Developmental regulation of B lymphocyte immune tolerance compartmentalizes clonal selection from receptor selection. Cell 1998, 92:173–182.


Immunology_Janeway

Immunology_Janeway. Nemazee, D.: Receptor editing in lymphocyte development and central tolerance. Nat. Rev. Immunol. 2006, 6:728–740. Prak, E.L., and Weigert, M.: Light-chain replacement—a new model for antibody gene rearrangement. J. Exp. Med. 1995, 182:541–548. 8-7 Lymphocytes that encounter sufficient quantities of self antigens for the first time in the periphery are eliminated or inactivated. Cyster, J.G., Hartley, S.B., and Goodnow, C.C.: Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature 1994, 371:389–395. Goodnow, C.C., Crosbie, J., Jorgensen, H., Brink, R.A., and Basten, A.: Induction of self-tolerance in mature peripheral B lymphocytes. Nature 1989, 342:385–391. Lam, K.P., Kuhn, R., and Rajewsky, K.: In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 1997, 90:1073–1083.


Immunology_Janeway

Immunology_Janeway. Lam, K.P., Kuhn, R., and Rajewsky, K.: In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 1997, 90:1073–1083. Russell, D.M., Dembic, Z., Morahan, G., Miller, J.F.A.P., Burki, K., and Nemazee, D.: Peripheral deletion of self-reactive B cells. Nature 1991, 354:308–311. Steinman, R.M., and Nussenzweig, M.C.: Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc. Natl Acad. Sci. USA 2002, 99:351–358. 8-8 Immature B cells arriving in the spleen turn over rapidly and require cytokines and positive signals through the B-cell receptor for maturation and survival. Allman, D.M., Ferguson, S.E., Lentz, V.M., and Cancro, M.P.: Peripheral B cell maturation. II. Heat-stable antigenhi splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells. J. Immunol. 1993, 151:4431–4444.


Immunology_Janeway

Immunology_Janeway. Harless, S.M., Lentz, V.M., Sah, A.P., Hsu, B.L., Clise-Dwyer, K., Hilbert, D.M., Hayes, C.E., and Cancro, M.P.: Competition for BLyS-mediated signaling through Bcmd/BR3 regulates peripheral B lymphocyte numbers. Curr. Biol. 2001, 11:1986–1989. Levine, M.H., Haberman, A.M., Sant’Angelo, D.B., Hannum, L.G., Cancro, M.P., Janeway, C.A., Jr., and Shlomchik, M.J.: A B-cell receptor-specific selection step governs immature to mature B cell differentiation. Proc. Natl Acad. Sci. USA 2000, 97:2743–2748. Loder, F., Mutschler, B., Ray, R.J., Paige, C.J., Sideras, P., Torres, R., Lamers, M.C., and Carsetti, R.: B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J. Exp. Med. 1999, 190:75–89. Rolink, A.G., Tschopp, J., Schneider, P., and Melchers, F.: BAFF is a survival and maturation factor for mouse B cells. Eur. J. Immunol. 2002, 32:2004–2010.


Immunology_Janeway

Immunology_Janeway. Rolink, A.G., Tschopp, J., Schneider, P., and Melchers, F.: BAFF is a survival and maturation factor for mouse B cells. Eur. J. Immunol. 2002, 32:2004–2010. Schiemann, B., Gommerman, J.L., Vora, K., Cachero, T.G., Shulga-Morskaya, S., Dobles, M., Frew, E., and Scott, M.L.: An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001, 293:2111–2114. Stadanlick, J.E., and Cancro, M.P.: BAFF and the plasticity of peripheral B cell tolerance. Curr. Opin. Immunol. 2008, 20:158–161. Wen, L., Brill-Dashoff, J., Shinton, S.A.,Asano, M., Hardy, R.R., and Hayakawa, K.: Evidence of marginal-zone B cell-positive selection in spleen. Immunity 2005, 23:297–308. 8-9 B-1 B cells are an innate lymphocyte subset that arises early in development Montecino-Rodriguez, E., and Dorshkind, K.: B-1 B cell development in the fetus and adult. Immunity 2012, 36:13–21.


Immunology_Janeway

Immunology_Janeway. 8-9 B-1 B cells are an innate lymphocyte subset that arises early in development Montecino-Rodriguez, E., and Dorshkind, K.: B-1 B cell development in the fetus and adult. Immunity 2012, 36:13–21. 8-10 T-cell progenitors originate in the bone marrow, but all the important events in their development occur in the thymus. Anderson, G., Moore, N.C., Owen, J.J.T., and Jenkinson, E.J.: Cellular interactions in thymocyte development. Annu. Rev. Immunol. 1996, 14:73–99. Carlyle, J.R., and Zúñiga-Pflücker, J.C.: Requirement for the thymus in α:β T lymphocyte lineage commitment. Immunity 1998, 9:187–197. Gordon, J., Wilson, V.A., Blair, N.F., Sheridan, J., Farley, A., Wilson, L., Manley, N.R., and Blackburn, C.C.: Functional evidence for a single endodermal origin for the thymic epithelium. Nat. Immunol. 2004, 5:546–553.


Immunology_Janeway

Immunology_Janeway. Nehls, M., Kyewski, B., Messerle, M., Waldschütz, R., Schüddekopf, K., Smith, A.J.H., and Boehm, T.: Two genetically separable steps in the differentiation of thymic epithelium. Science 1996, 272:886–889. Rodewald, H.R.: Thymus organogenesis. Annu. Rev. Immunol. 2008, 26:355–388. van Ewijk, W., Hollander, G., Terhorst, C., and Wang, B.: Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development 2000, 127:1583–1591. 8-11 Commitment to the T-cell lineage occurs in the thymus following Notch signaling. Pui, J.C., Allman, D., Xu, L., DeRocco, S., Karnell, F.G., Bakkour, S., Lee, J.Y., Kadesch, T., Hardy, R.R., Aster, J.C., et al.: Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 1999, 11:299–308. Radtke, F., Fasnacht, N., and Macdonald, H.R.: Notch signaling in the immune system. Immunity 2010, 32:14–27.


Immunology_Janeway

Immunology_Janeway. Radtke, F., Fasnacht, N., and Macdonald, H.R.: Notch signaling in the immune system. Immunity 2010, 32:14–27. Radtke, F., Wilson, A., Stark, G., Bauer, M., van Meerwijk, J., MacDonald, H.R., and Aguet, M.: Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 1999, 10:547–558. Rothenberg, E.V.: Transcriptional drivers of the T-cell lineage program. Curr. Opin. Immunol. 2012, 24:132–138. 8-12 T-cell precursors proliferate extensively in the thymus, but most die there. Shortman, K., Egerton, M., Spangrude, G.J., and Scollay, R.: The generation and fate of thymocytes. Semin. Immunol. 1990, 2:3–12. Surh, C.D., and Sprent, J.: T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 1994, 372:100–103. 8-13 Successive stages in the development of thymocytes are marked by changes in cell-surface molecules.


Immunology_Janeway

Immunology_Janeway. 8-13 Successive stages in the development of thymocytes are marked by changes in cell-surface molecules. Borowski, C., Martin, C., Gounari, F., Haughn, L., Aifantis, I., Grassi, F., and von Boehmer, H.: On the brink of becoming a T cell. Curr. Opin. Immunol. 2002, 14:200–206. Pang, S.S., Berry, R., Chen, Z., Kjer-Nielsen, L., Perugini, M.A., King, G.F., Wang, C., Chew, S.H., La Gruta, N.L., Williams, N.K., et al.: The structural basis for autonomous dimerization of the pre-T-cell antigen receptor. Nature 2010, 467:844–848. Saint-Ruf, C., Ungewiss, K., Groettrup, M., Bruno, L., Fehling, H.J., and von Boehmer, H.: Analysis and expression of a cloned pre-T-cell receptor gene. Science 1994, 266:1208–1212. Shortman, K., and Wu, L.: Early T lymphocyte progenitors. Annu. Rev. Immunol. 1996, 14:29–47. 8-14 Thymocytes at different developmental stages are found in distinct parts of the thymus.


Immunology_Janeway

Immunology_Janeway. Shortman, K., and Wu, L.: Early T lymphocyte progenitors. Annu. Rev. Immunol. 1996, 14:29–47. 8-14 Thymocytes at different developmental stages are found in distinct parts of the thymus. Benz, C., Heinzel, K., and Bleul, C.C.: Homing of immature thymocytes to the subcapsular microenvironment within the thymus is not an absolute requirement for T cell development. Eur. J. Immunol. 2004, 34:3652–3663. Bleul, C.C., and Boehm, T.: Chemokines define distinct microenvironments in the developing thymus. Eur. J. Immunol. 2000, 30:3371–3379. Nitta, T., Murata, S., Ueno, T., Tanaka, K., and Takahama, Y.: Thymic microenvironments for T-cell repertoire formation. Adv. Immunol. 2008, 99:59–94. Ueno, T., Saito F., Gray, D.H.D., Kuse, S., Hieshima, K., Nakano, H., Kakiuchi, T., Lipp, M., Boyd, R.L., and Takahama, Y.: CCR7 signals are essential for cortex– medulla migration of developing thymocytes. J. Exp. Med. 2004, 200:493–505.


Immunology_Janeway

Immunology_Janeway. 8-15 T cells with α:β or γ:δ receptors arise from a common progenitor. Fehling, H.J., Gilfillan, S., and Ceredig, R.: αβ/γδ lineage commitment in the thymus of normal and genetically manipulated mice. Adv. Immunol. 1999, 71:1–76. Hayday, A.C., Barber, D.F., Douglas, N., and Hoffman, E.S.: Signals involved in γδ T cell versus αβ T cell lineage commitment. Semin. Immunol. 1999, 11:239–249. Hayes, S.M., and Love, P.E.: Distinct structure and signaling potential of the γδ TCR complex. Immunity 2002, 16:827–838. Kang, J., and Raulet, D.H.: Events that regulate differentiation of αβTCR+ and γδ TCR+ T cells from a common precursor. Semin. Immunol. 1997, 9:171–179. Kreslavsky, T., Garbe, A.I., Krueger, A., and von Boehmer, H.: T cell receptor-instructed αβ versus γδ lineage commitment revealed by single-cell analysis. J. Exp. Med. 2008, 205:1173–1186.


Immunology_Janeway

Immunology_Janeway. Kreslavsky, T., Garbe, A.I., Krueger, A., and von Boehmer, H.: T cell receptor-instructed αβ versus γδ lineage commitment revealed by single-cell analysis. J. Exp. Med. 2008, 205:1173–1186. Lauritsen, J.P., Haks, M.C., Lefebvre, J.M., Kappes, D.J., and Wiest, D.L.: Recent insights into the signals that control αβ/γδ-lineage fate. Immunol. Rev. 2006, 209:176–190. Livak, F., Petrie, H.T., Crispe, I.N., and Schatz, D.G.: In-frame TCRδ gene rearrangements play a critical role in the αβ/γδ T cell lineage decision. Immunity 1995, 2:617–627. Xiong, N., and Raulet, D.H.: Development and selection of γδT cells. Immunol. Rev. 2007, 215:15–31. 8-16 T cells expressing γ:δ T-cell receptors arise in two distinct phases during development. Carding, S.R., and Egan, P.J.: γδ T cells: functional plasticity and heterogeneity. Nat. Rev. Immunol. 2002, 2:336–345.


Immunology_Janeway

Immunology_Janeway. Carding, S.R., and Egan, P.J.: γδ T cells: functional plasticity and heterogeneity. Nat. Rev. Immunol. 2002, 2:336–345. Ciofani, M., Knowles, G.C., Wiest, D.L., von Boehmer, H., and Zúñiga-Pflücker, J.C.: Stage-specific and differential notch dependency at the α:β and γ:δ T lineage bifurcation. Immunity 2006, 25:105–116. Dunon, D., Courtois, D., Vainio, O., Six, A., Chen, C.H., Cooper, M.D., Dangy, J.P., and Imhof, B.A.: Ontogeny of the immune system: γ:δ and α:β T cells migrate from thymus to the periphery in alternating waves. J. Exp. Med. 1997, 186:977–988. Haas, W., Pereira, P., and Tonegawa, S.: Gamma/delta cells. Annu. Rev. Immunol. 1993, 11:637–685. Lewis, J.M., Girardi, M., Roberts, S.J., Barbee, S.D., Hayday, A.C., and Tigelaar, R.E.: Selection of the cutaneous intraepithelial γδ+ T cell repertoire by a thymic stromal determinant. Nat. Immunol. 2006, 7:843–850.


Immunology_Janeway

Immunology_Janeway. Narayan, K., Sylvia, K.E., Malhotra, N., Yin, C.C., Martens, G., Vallerskog, T., Kornfeld, H., Xiong, N., Cohen, N.R., Brenner, M.B., et al.: Intrathymic programming of effector fates in three molecularly distinct gamma:delta T cell subtypes. Nat. Immunol. 2012, 13:511–518. Strid, J., Tigelaar, R.E., and Hayday, A.C.: Skin immune surveillance by T cells—a new order? Semin. Immunol. 2009, 21:110–120. 8-17 Successful synthesis of a rearranged β chain allows the production of β-chain gene rearrangement. Borowski, C., Li, X., Aifantis, I., Gounari, F., and von Boehmer, H.: Pre-TCRα and TCRα are not interchangeable partners of TCRβ during T lymphocyte development. J. Exp. Med. 2004, 199:607–615. Dudley, E.C., Petrie, H.T., Shah, L.M., Owen, M.J., and Hayday, A.C.: T-cell receptor β chain gene rearrangement and selection during thymocyte development in adult mice. Immunity 1994, 1:83–93.


Immunology_Janeway

Immunology_Janeway. Dudley, E.C., Petrie, H.T., Shah, L.M., Owen, M.J., and Hayday, A.C.: T-cell receptor β chain gene rearrangement and selection during thymocyte development in adult mice. Immunity 1994, 1:83–93. Philpott, K.I., Viney, J.L., Kay, G., Rastan, S., Gardiner, E.M., Chae, S., Hayday, A.C., and Owen, M.J.: Lymphoid development in mice congenitally lacking T cell receptor αβ-expressing cells. Science 1992, 256:1448–1453. von Boehmer, H., Aifantis, I., Azogui, O., Feinberg, J., Saint-Ruf, C., Zober, C., Garcia, C., and Buer, J.: Crucial function of the pre-T-cell receptor (TCR) in TCRβ selection, TCRβ allelic exclusion and α:β versus γ:δ lineage commitment. Immunol. Rev. 1998, 165:111–119. 8-18 T-cell α-chain genes undergo successive rearrangements until positive selection or cell death intervenes. Buch, T., Rieux-Laucat, F., Förster, I., and Rajewsky, K.: Failure of HY-specific thymocytes to escape negative selection by receptor editing. Immunity 2002, 16:707–718.


Immunology_Janeway

Immunology_Janeway. Buch, T., Rieux-Laucat, F., Förster, I., and Rajewsky, K.: Failure of HY-specific thymocytes to escape negative selection by receptor editing. Immunity 2002, 16:707–718. Hardardottir, F., Baron, J.L., and Janeway, C.A., Jr.: T cells with two functional antigen-specific receptors. Proc. Natl Acad. Sci. USA 1995, 92:354–358. Huang, C.-Y., Sleckman, B.P., and Kanagawa, O.: Revision of T cell receptor α chain genes is required for normal T lymphocyte development. Proc. Natl Acad. Sci. USA 2005, 102:14356–14361. Marrack, P., and Kappler, J.: Positive selection of thymocytes bearing α:β T cell receptors. Curr. Opin. Immunol. 1997, 9:250–255. Padovan, E., Casorati, G., Dellabona, P., Meyer, S., Brockhaus, M., and Lanzavecchia, A.: Expression of two T-cell receptor α chains: dual receptor T cells. Science 1993, 262:422–424.


Immunology_Janeway

Immunology_Janeway. Padovan, E., Casorati, G., Dellabona, P., Meyer, S., Brockhaus, M., and Lanzavecchia, A.: Expression of two T-cell receptor α chains: dual receptor T cells. Science 1993, 262:422–424. Petrie, H.T., Livak, F., Schatz, D.G., Strasser, A., Crispe, I.N., and Shortman, K.: Multiple rearrangements in T-cell receptor α-chain genes maximize the production of useful thymocytes. J. Exp. Med. 1993, 178:615–622. 8-19 Only thymocytes whose receptors interact with self peptide:self MHC complexes can survive and mature. Hogquist, K.A., Tomlinson, A.J., Kieper, W.C., McGargill, M.A., Hart, M.C., Naylor, S., and Jameson, S.C.: Identification of a naturally occurring ligand for thymic positive selection. Immunity 1997, 6:389–399. Kisielow, P., Teh, H.S., Blüthmann, H., and von Boehmer, H.: Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Nature 1988, 335:730–733.


Immunology_Janeway

Immunology_Janeway. Kisielow, P., Teh, H.S., Blüthmann, H., and von Boehmer, H.: Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Nature 1988, 335:730–733. 8-20 Positive selection acts on a repertoire of T-cell receptors with inherent specificity for MHC molecules. Marrack, P., Scott-Browne, J.P., Dai, S., Gapin, L., and Kappler, J.W.: Evolutionarily conserved amino acids that control TCR-MHC interaction. Annu. Rev. Immunol. 2008, 26:171–203. Merkenschlager, M., Graf, D., Lovatt, M., Bommhardt, U., Zamoyska, R., and Fisher, A.G.: How many thymocytes audition for selection? J. Exp. Med. 1997, 186:1149–1158. Scott-Browne, J.P., White, J., Kappler, J.W., Gapin, L., and Marrack, P.: Germlineencoded amino acids in the αβ T-cell receptor control thymic selection. Nature 2009, 458:1043–1046. Zerrahn, J., Held, W., and Raulet, D.H.: The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 1997, 88:627–636.


Immunology_Janeway

Immunology_Janeway. Zerrahn, J., Held, W., and Raulet, D.H.: The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 1997, 88:627–636. 8-21 Positive selection coordinates the expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the T cell. Egawa, T., and Littman, D.R.: ThPOK acts late in specification of the helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic T cell lineage. Nat. Immunol. 2008, 9:1131–1139. He, X., Xi, H., Dave, V.P., Zhang, Y., Hua, X., Nicolas, E., Xu, W., Roe, B.A., and Kappes, D.J.: The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 2005, 433:826–833. Singer, A., Adoro, S., and Park, J.H.: Lineage fate and intense debate: myths, models and mechanisms of CD4versus CD8-lineage choice. Nat. Rev. Immunol. 2008, 8:788–801.


Immunology_Janeway

Immunology_Janeway. Singer, A., Adoro, S., and Park, J.H.: Lineage fate and intense debate: myths, models and mechanisms of CD4versus CD8-lineage choice. Nat. Rev. Immunol. 2008, 8:788–801. von Boehmer, H., Kisielow, P., Lishi, H., Scott, B., Borgulya, P., and Teh, H.S.: The expression of CD4 and CD8 accessory molecules on mature T cells is not random but correlates with the specificity of the α:β receptor for antigen. Immunol. Rev. 1989, 109:143–151. 8-22 Thymic cortical epithelial cells mediate positive selection of developing thymocytes. Cosgrove, D., Chan, S.H., Waltzinger, C., Benoist, C., and Mathis, D.: The thymic compartment responsible for positive selection of CD4+ T cells. Int. Immunol. 1992, 4:707–710. Ernst, B.B., Surh, C.D., and Sprent, J.: Bone marrow-derived cells fail to induce positive selection in thymus reaggregation cultures. J. Exp. Med. 1996, 183:1235–1240.


Immunology_Janeway

Immunology_Janeway. Ernst, B.B., Surh, C.D., and Sprent, J.: Bone marrow-derived cells fail to induce positive selection in thymus reaggregation cultures. J. Exp. Med. 1996, 183:1235–1240. Murata, S., Sasaki, K., Kishimoto, T., Niwa, S.-I., Hayashi, H., Takahama, Y., and Tanaka, K.: Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 2007, 316:1349–1353. Nakagawa, T., Roth, W., Wong, P., Nelson, A., Farr, A., Deussing, J., Villadangos, J.A., Ploegh, H., Peters, C., and Rudensky, A.Y.: Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 1998, 280:450–453. 8-23 T cells that react strongly with ubiquitous self antigens are deleted in the thymus. Anderson, M.S., Venanzi, E.S., Klein, L., Chen, Z., Berzins, S.P., Turley, S.J., von Boehmer, H., Bronson, R., Dierich, A., Benoist, C., et al.: Projection of an immunological self shadow within the thymus by the aire protein. Science 2002, 298:1395–1401.


Immunology_Janeway

Immunology_Janeway. Kishimoto, H., and Sprent, J.: Negative selection in the thymus includes semimature T cells. J. Exp. Med. 1997, 185:263–271. Zal, T., Volkmann, A., and Stockinger, B.: Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self antigen. J. Exp. Med. 1994, 180:2089–2099. 8-24 Negative selection is driven most efficiently by bone marrow-derived antigen-presenting cells. Anderson, M.S., and Su, M.A.: Aire and T cell development. Curr. Opin. Immunol. 2011, 23:198–206. McCaughtry, T.M., Baldwin, T.A., Wilken, M.S., and Hogquist, K.A.: Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla. J. Exp. Med. 2008, 205:2575–2584. Sprent, J., and Webb, S.R.: Intrathymic and extrathymic clonal deletion of T cells. Curr. Opin. Immunol. 1995, 7:196–205. Webb, S.R., and Sprent, J.: Tolerogenicity of thymic epithelium. Eur. J. Immunol. 1990, 20:2525–2528.


Immunology_Janeway

Immunology_Janeway. Webb, S.R., and Sprent, J.: Tolerogenicity of thymic epithelium. Eur. J. Immunol. 1990, 20:2525–2528. 8-25 The specificity and/or the strength of signals for negative and positive selection must differ. Alberola-Ila, J., Hogquist, K.A., Swan, K.A., Bevan, M.J., and Perlmutter, R.M.: Positive and negative selection invoke distinct signaling pathways. J. Exp. Med. 1996, 184:9–18. Ashton-Rickardt, P.G., Bandeira, A., Delaney, J.R., Van Kaer, L., Pircher, H.P., Zinkernagel, R.M., and Tonegawa, S.: Evidence for a differential avidity model of T-cell selection in the thymus. Cell 1994, 76:651–663. Bommhardt, U., Scheuring, Y., Bickel, C., Zamoyska, R., and Hunig, T.: MEK activity regulates negative selection of immature CD4+CD8+ thymocytes. J. Immunol. 2000, 164:2326–2337. Hogquist, K.A., Jameson, S.C., Heath, W.R., Howard, J.L., Bevan, M.J., and Carbone, F.R.: T-cell receptor antagonist peptides induce positive selection. Cell 1994, 76:17–27.


Immunology_Janeway

Immunology_Janeway. Hogquist, K.A., Jameson, S.C., Heath, W.R., Howard, J.L., Bevan, M.J., and Carbone, F.R.: T-cell receptor antagonist peptides induce positive selection. Cell 1994, 76:17–27. 8-26 Self-recognizing regulatory T cells and innate T cells develop in the thymus. Jordan, M.S., Boesteanu, A., Reed, A.J., Petrone, A.L., Holenbeck, A.E., Lerman, M.A., Naji, A., and Caton, A.J.: Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2001, 2:301–306. Moran, A.E., and Hogquist, K.A.: T-cell receptor affinity in thymic development. Immunology 2012, 135:261–267. Zheng, Y., and Rudensky, A.Y.: Foxp3 in control of the regulatory T cell lineage. Nat. Immunol. 2007, 8:457–462. 8-27 The final stage of T-cell maturation occurs in the thymic medulla.


Immunology_Janeway

Immunology_Janeway. Zheng, Y., and Rudensky, A.Y.: Foxp3 in control of the regulatory T cell lineage. Nat. Immunol. 2007, 8:457–462. 8-27 The final stage of T-cell maturation occurs in the thymic medulla. Matloubian, M., Lo, C.G., Cinamon, G., Lesneski, M.J., Xu, Y., Brinkmann, V., Allende, M.L., Proia, R.L., and Cyster, J.G.: Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004, 427:355–360. Zachariah, M.A., and Cyster, J.G.: Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 2010, 328:1129–1135. 8-28 T cells that encounter sufficient quantities of self antigens for the first time in the periphery are eliminated or inactivated. Fink, P.J., and Hendricks, D.W.: Post-thymic maturation: young T cells assert their individuality. Nat. Rev. Immunol. 2011, 11:544–549.


Immunology_Janeway

Immunology_Janeway. Fink, P.J., and Hendricks, D.W.: Post-thymic maturation: young T cells assert their individuality. Nat. Rev. Immunol. 2011, 11:544–549. Steinman, R.M., and Nussenzweig, M.C.: Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc. Natl Acad. Sci. USA 2002, 99:351–358. Xing, Y., and Hogquist, K.A.: T-cell tolerance: central and peripheral. Cold Spring Harb. Perspect. Biol. 2012, 4.pii:a006957


Immunology_Janeway

Immunology_Janeway. An adaptive immune response is initiated when a pathogen overwhelms innate defense mechanisms. As the pathogen replicates and antigen accumulates, sensor cells of the innate immune system become activated to trigger the adaptive immune response. While some infections may be dealt with solely by innate immunity, as discussed in Chapters 2 and 3, host defense against most pathogens, almost by definition, requires recruitment of adaptive immunity. This is shown by the immunodeficiency syndromes that are associated with failure of particular parts of the adaptive immune response; these will be discussed in Chapter 13. In the next three chapters, we will learn how the adaptive immune response involving antigen-specific T cells and B cells is initiated and deployed. T-cell responses that lead to cellular immunity will be considered first, in this chapter; and B-cell responses that lead to antibody-mediated, or humoral, immunity will be considered in Chapter 10. In Chapter 11 we will


Immunology_Janeway

Immunology_Janeway. lead to cellular immunity will be considered first, in this chapter; and B-cell responses that lead to antibody-mediated, or humoral, immunity will be considered in Chapter 10. In Chapter 11 we will consider the dynamics of T-cell and B-cell responses in the context of their integration with innate immunity and how this culminates in one of the most important features of adaptive immunity—immunological memory.


Immunology_Janeway

Immunology_Janeway. Once T cells have completed their primary development in the thymus, they enter the bloodstream. On reaching a secondary lymphoid organ, they leave the blood to migrate through the lymphoid tissue, returning via the lymphatics to the bloodstream to recirculate between blood and secondary lymphoid tissues. Mature recirculating T cells that have not yet encountered their specific antigens are known as naive T cells. To participate in an adaptive immune response, a naive T cell must meet its specific antigen, presented to it as a peptide:MHC complex on the surface of an antigen-presenting cell, and be induced to proliferate and differentiate into progeny with new activities that contribute to removal of antigen. These progeny cells are called effector T cells and, unlike naive T cells, perform their functions as soon as they encounter development and function of secondary lymphoid organs—sites for the initiation of adaptive immune responses.


Immunology_Janeway

Immunology_Janeway. priming of naive T cells by pathogen-activated dendritic cells. General properties of effector T cells and their cytokines. T-cell-mediated cytotoxicity. their specific antigen on other cells—generally without requirement for further differentiation. Because of their requirement to recognize peptide antigens presented by MHC molecules, all effector T cells act on other host cells, not on the pathogen itself. The cells on which effector T cells act will be referred to as their target cells.


Immunology_Janeway

Immunology_Janeway. On recognizing antigen, naive T cells differentiate into several functional classes of effector T cells that are specialized for different activities. CD8 T cells recognize pathogen peptides presented by MHC class I molecules, and naive CD8 T cells differentiate into cytotoxic effector T cells that recognize and kill infected cells. CD4 T cells have a more flexible repertoire of effector activities. After recognizing pathogen peptides presented by MHC class II molecules, naive CD4 T cells can differentiate down distinct pathways that generate effector subsets with different immunological functions. The main CD4 effector subsets are TH1, TH2, TH17, and TFH, which activate their target cells; and regulatory T cells, or Treg cells, which inhibit the extent of immune activation.


Immunology_Janeway

Immunology_Janeway. Effector T cells differ from their naive precursors in ways that equip them to respond quickly and efficiently when they encounter specific antigen on target cells. Among the changes that occur are alterations in the expression of surface molecules that alter the patterns of migration of effector T cells, directing them to exit the secondary lymphoid tissues and move to sites of inflammation where pathogens have entered, or to B-cell zones within secondary lymphoid tissues, where they help generate pathogen-specific antibodies. The interactions with target cells in these sites are mediated both by direct T-cell–target cell contact and the release of cytokines, which can act locally on target cells; and at a distance to orchestrate the clearance of antigen. Some of the effector functions of T cells will be considered in this chapter; others will be discussed in Chapters 10 and 11 in the context of T-cell help for B cells and heightened activation of effector cells of the innate immune


Immunology_Janeway

Immunology_Janeway. T cells will be considered in this chapter; others will be discussed in Chapters 10 and 11 in the context of T-cell help for B cells and heightened activation of effector cells of the innate immune system.


Immunology_Janeway

Immunology_Janeway. The activation and clonal expansion of a naive T cell on its initial encounter with antigen is often called priming, to distinguish this process from the responses of effector T cells to antigen on their target cells and the responses of primed memory T cells. The initiation of adaptive immunity is one of the most compelling narratives in immunology. As we will learn, the activation of naive T cells is controlled by a variety of signals. The primary signal that a naive T cell must recognize is antigen in the form of a peptide:MHC complex on the surface of a specialized antigen-presenting cell, as discussed in Chapter 6. Activation of the naive T cell also requires that it recognize co-stimulatory molecules that are displayed by antigen-presenting cells. Finally, cytokines that control differentiation into different types of effector cells are delivered to the activated naive T cell. All these events are set in motion by earlier signals that arise from the initial detection of the


Immunology_Janeway

Immunology_Janeway. differentiation into different types of effector cells are delivered to the activated naive T cell. All these events are set in motion by earlier signals that arise from the initial detection of the pathogens by the innate immune system. Microbe-derived signals are delivered to cells of the innate immune system by receptors such as the Toll-like receptors (TLRs), which recognize microbe-associated molecular patterns, or MAMPs, that signify the presence of nonself (see Chapters 2 and 3). As we will see in this chapter, these signals are essential to activate antigen-presenting cells so that they are able, in turn, to activate naive T cells.


Immunology_Janeway

Immunology_Janeway. By far the most important antigen-presenting cells in the activation of naive T cells are dendritic cells, whose major function is to ingest and present antigen. Tissue dendritic cells take up antigen at sites of infection and are activated as part of the innate immune response. This induces their migration to local lymphoid tissue and their maturation into cells that are highly effective at presenting antigen to recirculating naive T cells. In the first part of this chapter we will consider the development and organization of secondary lymphoid tissues and discuss how naive T cells and dendritic cells meet in these sites to initiate adaptive immunity. Development and function of secondary lymphoid organs—sites for the initiation of adaptive immune responses.


Immunology_Janeway

Immunology_Janeway. As discussed in Chapter 8, the primary lymphoid organs—the thymus and bone marrow—are the tissue sites where antigenic receptor repertoires of T and B cells, respectively, are selected. Adaptive immune responses are initiated in the secondary lymphoid organs—lymph nodes, spleen, and the mucosa-associated lymphoid tissues (MALTs) such as the Peyer’s patches in the gut. The architecture of these tissues is similar throughout the body and is structured to provide a crossroads for the interaction of rare clonal precursors of recirculating T and B cells with their cognate antigens—whether delivered by dendritic cells in the case of T cells, or as free antigens in the case of B cells. In view of the rarity of naive T cells that recognize a specific peptide:MHC complex—roughly 50–500 cells in the entire immune repertoire of approximately 100 million T cells in the mouse—and the large area over which an infectious agent can invade, the antigens derived from the pathogen, or in some instances


Immunology_Janeway

Immunology_Janeway. entire immune repertoire of approximately 100 million T cells in the mouse—and the large area over which an infectious agent can invade, the antigens derived from the pathogen, or in some instances the pathogen itself, must be brought from sites of entry to secondary lymphoid organs to facilitate their recognition by lymphocytes. In this part of the chapter we shall first consider the development and structure of secondary lymphoid organs that enable these interactions. We shall then discuss how naive T cells are directed to exit the blood and enter the lymphoid organs. This will be followed by considering how dendritic cells pick up antigen and travel to local lymphoid organs, where they can both present antigen to T cells and activate them.


Immunology_Janeway

Immunology_Janeway. 9-1 T and B lymphocytes are found in distinct locations in secondary lymphoid tissues. The various secondary lymphoid organs are organized roughly along the same lines (see Chapter 1), with distinct areas in which B cells and T cells are concentrated—the B-cell and T-cell zones. They also contain macrophages, dendritic cells, and nonleukocyte stromal cells. In the case of the spleen, which is specialized for the capture of antigens that enter the bloodstream, the lymphoid tissue component is called the white pulp (Fig. 9.1).


Immunology_Janeway

Immunology_Janeway. Fig. 9.1 Secondary lymphoid tissues serve as anatomical crossroads for interactions of antigens and lymphocytes. secondary lymphoid tissues are specialized to serve as sites that facilitate interactions between lymphocytes and antigens. In lymph nodes (upper panel), antigen (denoted by red dots) is delivered in lymph either free or as cargo of dendritic cells that have taken up the antigen in the tissues drained by the lymph node. The antigen is conducted via afferent lymphatics to the subcapsular sinus, from which it is delivered to T-cell zones, where T cells can recognize it on the surface of dendritic cells; or, in the case of B cells, it is detected as a free antigen at the border of the T-cell zone and B-cell follicles. T and B cells enter the lymph node via high endothelial venules (hevs) in T-cell zones, and then diverge into T-cell and B-cell zones. In the spleen (middle panel), antigen is delivered via arterioles that branch from the central arteriole to the marginal sinus,


Immunology_Janeway

Immunology_Janeway. (hevs) in T-cell zones, and then diverge into T-cell and B-cell zones. In the spleen (middle panel), antigen is delivered via arterioles that branch from the central arteriole to the marginal sinus, which is the boundary between the white pulp and red pulp, with which the marginal sinus communicates. In the marginal sinus, antigen can be taken up by marginal zone B cells, macrophages, or dendritic cells, which can transport antigen into either T-cell zones (periarteriolar lymphoid sheath, or paLs) or B-cell follicles. T and B cells enter the spleen via the same route as antigen, and leave the marginal sinus to travel to either the paLs or the B-cell follicles. In the intestines (lower panel), antigens are transported from the lumen via the microfold or M cells—specialized epithelium that overlays peyer’s patches—to dendritic cells that reside in the subepithelial dome. antigen-loaded dendritic cells are then surveyed by T cells in T-cell zones, and if the antigens they bear are not


Immunology_Janeway

Immunology_Janeway. overlays peyer’s patches—to dendritic cells that reside in the subepithelial dome. antigen-loaded dendritic cells are then surveyed by T cells in T-cell zones, and if the antigens they bear are not recognized by T cells locally, the dendritic cells can migrate to mesenteric lymph nodes to be further surveyed. as for lymph nodes, T and B cells enter the peyer’s patches via hevs in the T-cell zones.


Immunology_Janeway

Immunology_Janeway. Each area of white pulp is demarcated from the red pulp by a marginal sinus, a vascular network that is formed from branches of the central arteriole. Circulating T and B cells are initially delivered to the marginal sinus, which is a highly organized region of cells that is specialized for the capture of blood-borne antigens or intact microbes, such as viruses and bacteria. It is rich in macrophages and contains a unique population of B cells, the marginal zone B cells, which do not recirculate. Pathogens reaching the bloodstream are efficiently trapped in the marginal zone by macrophages, and it could be that marginal zone B cells are adapted to provide the first responses to such pathogens.


Immunology_Janeway

Immunology_Janeway. From the marginal sinus, T and B cells migrate centrally toward the central arteriole, where they bifurcate into T-cell zones that are clustered around the central arteriole—the so-called periarteriolar lymphoid sheath (PALS)— and B-cell zones, or follicles, that are located more peripherally. Some follicles may contain germinal centers, in which B cells involved in an adaptive immune response are proliferating and undergoing somatic hypermutation (see Section 1-16). The antigen-driven production of germinal centers will be described in detail when we consider B-cell responses in Chapter 10.


Immunology_Janeway

Immunology_Janeway. Other types of cells are found within the B-cell and T-cell areas. The B-cell zone contains a network of follicular dendritic cells (FDCs), which are concentrated mainly in the area of the follicle most distant from the central arteriole. FDCs have long processes that are in contact with B cells. FDCs are a distinct type of cell from the dendritic cells we encountered previously (see Section 1-3), in that they are not leukocytes and are not derived from bone marrow precursors; in addition, they are not phagocytic and do not express MHC class II proteins. FDCs are specialized for the capture of antigen in the form of immune complexes—complexes of antigen, antibody, and complement. The immune complexes are not internalized but remain intact on the surface of the FDC for prolonged periods of time, where the antigen can be recognized by B cells. FDCs are also important in the development of B-cell follicles.


Immunology_Janeway

Immunology_Janeway. T-cell zones contain a network of bone marrow-derived dendritic cells, sometimes known as interdigitating dendritic cells from the way in which their processes interweave among T cells. There are two major subtypes of these dendritic cells, distinguished by characteristic cell-surface proteins: one expresses the α chain of CD8, whereas the other is CD8-negative but expresses CD11b:CD18, an integrin that is also expressed by macrophages.


Immunology_Janeway

Immunology_Janeway. As in the spleen, the T cells and B cells in lymph nodes are organized into discrete T-cell and B-cell areas (see Fig. 9.1). B-cell follicles have a similar structure and composition to those in the spleen and are located just under the outer capsule of the lymph node. T-cell zones surround the follicles in the paracortical areas. Unlike the spleen, lymph nodes have connections to both the blood system and the lymphatic system. Lymph conducted to lymph nodes by afferent lymphatic vessels enters into the subcapsular space, which is also known as the marginal sinus, and brings in antigen and antigen-bearing dendritic cells from the tissues. T and B cells enter the lymph node via specialized blood vessels called high endothelial venules (HEVs) that are found in T-cell zones, as will be discussed further in Section 9-3.


Immunology_Janeway

Immunology_Janeway. The mucosa-associated lymphoid tissues (MALTs) are associated with the body’s epithelial surfaces, which provide physical barriers against infection. Peyer’s patches are part of the MALT and are lymph node-like structures interspersed at intervals just beneath the gut epithelium. They have B-cell follicles and T-cell zones (see Fig. 9.1), and the epithelium overlying them contains specialized M cells that are adapted to channel antigens and pathogens directly from the gut lumen to the underlying lymphoid tissue (see Section 1-16 and Chapter 12). Peyer’s patches and similar tissue present in the tonsils provide specialized sites where B cells can become committed to the synthesis of IgA. The mucosal immune system is discussed in more detail in Chapter 12. 9-2 The development of secondary lymphoid tissues is controlled by lymphoid tissue inducer cells and proteins of the tumor necrosis factor family.


Immunology_Janeway

Immunology_Janeway. Before discussing how T cells and B cells become partitioned into their respective zones in secondary lymphoid organs, we shall briefly look at how these organs develop in the first place. Lymphatic vessels are formed during embryonic development from endothelial cells that originate in blood vessels. Some endothelial cells in the early venous system begin to express the homeobox transcription factor Prox1. These cells bud from the vein, migrate away, and reassociate to form a parallel network of lymphatic vessels. Mice lacking Prox1 have normal arteries and veins, but fail to form a lymphatic system, showing this factor to be critical in establishing the identity of lymphatic endothelium. As the lymphatic vessels form, hematopoietic cells called lymphoid tissue inducer (LTi) cells arise in the fetal liver and are carried in the bloodstream to sites of prospective lymph nodes and Peyer’s patches. LTi cells initiate the formation of lymph nodes and Peyer’s patches by interacting with


Immunology_Janeway

Immunology_Janeway. in the fetal liver and are carried in the bloodstream to sites of prospective lymph nodes and Peyer’s patches. LTi cells initiate the formation of lymph nodes and Peyer’s patches by interacting with stromal cells and inducing the production of cytokines and chemokines, which recruit other lymphoid cells to these sites. Members of the tumor necrosis factor (TNF)/ TNF receptor (TNFR) family of cytokines turn out to be critically involved in the interactions between LTi cells and stromal cells.


Immunology_Janeway

Immunology_Janeway. The role of this family of cytokines in the formation of secondary lymphoid organs has been demonstrated in a series of studies involving knockout mice in which either the TNF-family ligand or its receptor was inactivated (Fig. 9.2). These knockout mice have complicated phenotypes, which is partly due to the fact that individual TNF-family proteins can bind to multiple receptors and, conversely, many receptors can bind more than one ligand. In addition, it seems clear that there is some overlapping function or cooperation between TNF-family proteins. Nonetheless, some general conclusions can be drawn.


Immunology_Janeway

Immunology_Janeway. Lymph-node development depends on the expression of TNF-family proteins known as the lymphotoxins (LTs), and different types of lymph nodes depend on signals from different LTs. LT-α3, a soluble homotrimer of the LT-α chain, supports the development of cervical and mesenteric lymph nodes, and possibly lumbar and sacral lymph nodes. All these lymph nodes drain mucosal sites. LT-α3 probably exerts its effects by binding to TNFR-I. The membrane-bound heterotrimer consisting of two molecules of LT-α and one molecule of the distinct transmembrane protein LT-β (that is, LT-α2:β1), often known as LT-β, binds only to the LT-β receptor and supports the development of all the other lymph nodes. Peyer’s patches also do not form in the absence of LT-β. The effects of the LT knockouts are not reversible in adult animals; there are certain critical developmental periods during which the absence or inhibition of these LT-family proteins will permanently prevent the development of lymph nodes and


Immunology_Janeway

Immunology_Janeway. in adult animals; there are certain critical developmental periods during which the absence or inhibition of these LT-family proteins will permanently prevent the development of lymph nodes and Peyer’s patches.


Immunology_Janeway

Immunology_Janeway. LTi cells express LT-β, which engages the LT-β receptors on stromal cells in the prospective lymphoid site, activating the non-canonical NFκB pathway


Immunology_Janeway

Immunology_Janeway. Fig. 9.2 The role of TNF family members in the development of peripheral lymphoid organs. The role of TnF family members in the development of peripheral lymphoid organs has been deduced mainly from the study of knockout mice deficient in one or more TnF-family ligands or receptors. some receptors bind more than one ligand, and some ligands bind more than one receptor, complicating elucidation of the effects of their deletion. (note that receptors are named for the first ligand known to bind them.) The defects are organized here with respect to the two main receptors, TnFr-I and the LT-β receptor, and their ligands, TnF-α and the lymphotoxins (LTs). note that in some cases, the losses of individual ligands out of several that bind the same receptor lead to different respective phenotypes, as indicated in the figure. This is due to the ability of the different ligands to bind different sets of receptors. The LT-α protein chain contributes to two distinct ligands, the trimer LT-α3 and


Immunology_Janeway

Immunology_Janeway. as indicated in the figure. This is due to the ability of the different ligands to bind different sets of receptors. The LT-α protein chain contributes to two distinct ligands, the trimer LT-α3 and the heterodimer LT-α2:β1, each of which acts through a distinct receptor. In general, signaling through the LT-β receptor is required for lymph-node and follicular dendritic cell (FdC) development and for normal splenic architecture, whereas signaling through TnFr-I is also required for FdCs and normal splenic architecture but not for lymph-node development.


Immunology_Janeway

Immunology_Janeway. Fig. 9.3 The development of secondary lymphoid organs is orchestrated by chemokines. The cellular organization of lymphoid organs is initiated by stromal cells and vascular endothelial cells, which secrete the chemokine CCL21 (first panel). dendritic cells with CCr7—a receptor for CCL21—are attracted to the site of the developing lymph node by CCL21 (second panel); it is not known whether at the earliest stages of lymph-node development immature dendritic cells enter from the bloodstream or via the lymphatics, as they do later in life. once in the lymph node, the dendritic cells express the chemokine CCL19, which is also bound by CCr7. Together, the chemokines secreted by stromal cells and dendritic cells attract T cells to the developing lymph node (third panel). The same combination of chemokines also attracts B cells into the developing lymph node (fourth panel). The B cells are able to either induce the differentiation of the nonleukocyte FdCs (which are a lineage distinct from


Immunology_Janeway

Immunology_Janeway. chemokines also attracts B cells into the developing lymph node (fourth panel). The B cells are able to either induce the differentiation of the nonleukocyte FdCs (which are a lineage distinct from the bone marrow-derived dendritic cells) or direct their recruitment into the lymph node. once present, the FdCs secrete CXCL13, a chemokine that is a chemoattractant for B cells. The production of CXCL13 drives the organization of B cells into discrete B-cell areas (follicles) around the FdCs and contributes to the further recruitment of B cells from the circulation into the lymph node (fifth panel).


Immunology_Janeway

Immunology_Janeway. (see Section 7-23). This induces the stromal cells to express adhesion molecules and chemokines such as CXCL13 (B-lymphocyte chemokine, BLC), which in turn recruits more LTi cells, which have receptors for these molecules, eventually generating large clusters of cells that will become lymph nodes or Peyer’s patches. The chemokines also attract cells such as lymphocytes and other hematopoietic-lineage cells with appropriate receptors to populate the forming lymphoid organ. The principles, and even some of the molecules, underlying the development of secondary lymphoid organs in the fetus are very similar to those that maintain the organization of lymphoid organs in the adult, as we shall see in the next section.


Immunology_Janeway

Immunology_Janeway. Although the spleen will develop in mice deficient in any of the known TNF or TNFR family members, its architecture will be abnormal in many of these mutants (see Fig. 9.2). LT (most probably the membrane-bound LT-β) is required for the normal segregation of T-cell and B-cell zones in the spleen. TNF-α, binding to TNFR-I, also contributes to the organization of the white pulp: when TNF-α signals are disrupted, B cells surround T-cell zones in a ring rather than forming discrete follicles, and the marginal zones are not well defined.


Immunology_Janeway

Immunology_Janeway. Perhaps the most important role of TNF-α and TNFR-I in lymphoid organ development is in the development of FDCs, as these cells are lacking in mice with knockouts of either TNF-α or TNFR-I (see Fig. 9.2). The knockout mice do have lymph nodes and Peyer’s patches, because they express LTs, but these structures lack FDCs. LT-β is also required for FDC development: mice that cannot form LT-β or signal through its receptor lack normal FDCs in the spleen and any residual lymph nodes. Unlike the disruption of lymph-node development, the disorganized lymphoid architecture in the spleen is reversible if the missing TNF-family member is restored. B cells are the likely source of the LT-β, because normal B cells can restore FDCs and follicles when transferred to RAG-deficient recipients (which lack lymphocytes). 9-3 T and B cells are partitioned into distinct regions of secondary lymphoid tissues by the actions of chemokines.


Immunology_Janeway

Immunology_Janeway. Circulating T and B cells seed secondary lymphoid tissues from the blood by a common route, but are then directed into their respective compartments under the control of distinct chemokines that are produced by both stromal cells and bone marrow-derived cells resident in the Tand B-cell zones (Fig. 9.3). The localization of T cells into T-cell zones involves two chemokines, CCL19 (MIP-3β) and CCL21 (secondary lymphoid chemokine, SLC). Both of these bind the receptor CCR7, which is expressed by T cells; mice that lack CCR7 do not form normal T-cell zones and have impaired primary immune responses. CCL21 is produced by stromal cells of T-cell zones in secondary lymphoid tissues, and is displayed on endothelial cells of high endothelial venules (HEVs). Another source of CCL21 is interdigitating dendritic cells, which also produce CCL19 and are prominent in T-cell zones. Indeed, dendritic cells themselves express CCR7 and will localize to secondary lymphoid tissues even in RAG-deficient


Immunology_Janeway

Immunology_Janeway. dendritic cells, which also produce CCL19 and are prominent in T-cell zones. Indeed, dendritic cells themselves express CCR7 and will localize to secondary lymphoid tissues even in RAG-deficient mice, which lack lymphocytes and therefore defined T-cell zones. Thus, during normal lymph-node development, the T-cell zone might be organized first through the attraction of dendritic cells and T cells by CCL21 produced by stromal cells. This organization would then be reinforced by CCL21 and CCL19 secreted by resident dendritic cells, which in turn attract more T cells and migratory dendritic cells.


Immunology_Janeway

Immunology_Janeway. CXCL13B cells induce the differentiation of follicular dendritic cells, which in turn secrete the chemokine CXCL13 to attract more B cells B cells are initially attracted into the developing lymph node by the same chemokines


Immunology_Janeway

Immunology_Janeway. Like T cells, circulating B cells express CCR7, which initially directs them into the lymph node across HEVs. Because they also constitutively express the chemokine receptor CXCR5, they are then attracted to the follicles by the ligand for this receptor, CXCL13. The most likely source of CXCL13 is the FDC, possibly along with other follicular stromal cells. This is reminiscent of the expression of CXCL13 by stromal cells during the formation of the lymph node (Section 9-2). B cells are, in turn, the source of the LT that is required for the development of FDCs, which is reminiscent of LTi cells expressing the LT required to activate stromal cells. The reciprocal dependence of B cells and FDCs, and LTis and stromal cells, illustrates the complex web of interactions that organizes secondary lymphoid tissues. A subset of CD4 T cells called T follicular helper, or TFH, cells can also express CXCR5 following their activation by antigen, allowing them to enter B-cell follicles to


Immunology_Janeway

Immunology_Janeway. secondary lymphoid tissues. A subset of CD4 T cells called T follicular helper, or TFH, cells can also express CXCR5 following their activation by antigen, allowing them to enter B-cell follicles to participate in the formation of germinal centers (see Chapter 10).


Immunology_Janeway

Immunology_Janeway. 9-4 Naive T cells migrate through secondary lymphoid tissues, sampling peptide:MHC complexes on dendritic cells.


Immunology_Janeway

Immunology_Janeway. Naive T cells perpetually circulate from the bloodstream into lymph nodes, spleen, and mucosa-associated lymphoid tissues and back to the blood (see Fig. 1.21). This allows them to contact thousands of dendritic cells every day and sample the peptide:MHC complexes on the surfaces of these cells. Because of their high rates of recirculation and their concentration in T-cell zones where incoming dendritic cells dwell, each T cell has a high probability of encountering antigens derived from any pathogen that has set up an infection anywhere in the body (Fig. 9.4). Within hours of their arrival, naive T cells that do not encounter their specific antigen exit from the lymphoid tissue and reenter the bloodstream, where they continue to recirculate—via the efferent lymphatics in lymph nodes or MALTs, or directly back to the blood in the spleen, which has no connection with the lymphatic system.


Immunology_Janeway

Immunology_Janeway. When a naive T cell recognizes its specific antigen on the surface of an activated dendritic cell, however, it ceases to migrate. It remains in the T-cell zone,


Immunology_Janeway

Immunology_Janeway. Fig. 9.4 Naive T cells encounter antigen during their recirculation through peripheral lymphoid organs. naive T cells recirculate through peripheral lymphoid organs, such as a lymph node (shown here), entering from the arterial blood via the specialized vascular endothelium of high endothelial venules (hevs). entry into the lymph node is regulated by chemokines (not shown) that direct the T cells’ migration through the hev wall and into the paracortical areas, where the T cells encounter mature dendritic cells (top panel). Those T cells shown in green do not encounter their specific antigen; they receive a survival signal through their interaction with self peptide:self MhC complexes and IL-7, and leave the lymph node through the lymphatics to return to the circulation (second panel). T cells shown in blue encounter their specific antigen on the surface of mature dendritic cells; they lose their ability to exit from the node and become activated to proliferate and to differentiate


Immunology_Janeway

Immunology_Janeway. T cells shown in blue encounter their specific antigen on the surface of mature dendritic cells; they lose their ability to exit from the node and become activated to proliferate and to differentiate into effector T cells (third panel). after several days, these antigen-specific effector T cells regain the expression of receptors needed to exit from the node, leave via the efferent lymphatics, and enter the circulation in greatly increased numbers (bottom panel).


Immunology_Janeway

Immunology_Janeway. 20 4 6 8 Emigration of effector T cells Time after viral infection (days) Antigen-speciÿc T cells are detained transiently in the lymph node, where they become activated ActivationTrapping Number of antigen-speciÿc cells in efferent lymph


Immunology_Janeway

Immunology_Janeway. Fig. 9.5 Trapping and activation of antigen-specific naive T cells in lymphoid tissue. naive T cells entering the lymph node from the blood encounter antigen-presenting dendritic cells in T-cell zones. T cells that recognize their specific antigen bind stably to the dendritic cells and are activated through their T-cell receptors, resulting in their retention within the lymph node as they develop into effector T cells. By 5 days after the arrival of antigen, activated effector T cells are leaving the lymph node in large numbers via the efferent lymphatics. Lymphocyte recirculation and recognition are so effective that all the naive T cells in the peripheral circulation specific for a particular antigen can be trapped by that antigen in one node within 2 days.


Immunology_Janeway

Immunology_Janeway. Fig. 9.6 Lymphocyte entry into a lymph node from the blood occurs in distinct stages involving the activity of adhesion molecules, chemokines, and chemokine receptors. naive T cells are induced to roll along the surface of a high endothelial venule (hev) by the interactions of selectins expressed by the T cells with vascular addressins on the endothelial cell membranes. Chemokines present at the hev surface activate receptors on the T cell, and chemokine receptor signaling leads to an increase in the affinity of integrins on the T cell for the adhesion molecules expressed on the hev. This induces strong adhesion. after adhesion, the T cells follow gradients of chemokines to pass through the hev wall into the paracortical region of the lymph node.


Immunology_Janeway

Immunology_Janeway. where it proliferates for several days, undergoing clonal expansion and differentiation to give rise to effector T cells and memory cells of identical antigen specificity. At the end of this period, most effector T cells exit the lymphoid organ and reenter the bloodstream, through which they migrate to the sites of infection (see Chapter 11). Some effector T cells that are fated to interact with B cells migrate instead to B-cell zones, where they participate in the germinal center response (see Chapter 10).


Immunology_Janeway

Immunology_Janeway. The efficiency with which T cells screen antigen-presenting cells in lymph nodes is very high, as can be seen by the rapid trapping of antigen-specific T cells in a single lymph node containing antigen; within 48 hours, all antigen-specific T cells in the body can be trapped in the lymph node draining a site of antigen injection (Fig. 9.5). Such efficiency is crucial for the initiation of an adaptive immune response, as only one naive T cell in 105–106 is likely to be specific for a particular antigen, and adaptive immunity depends on the activation and expansion of these rare cells. 9-5 Lymphocyte entry into lymphoid tissues depends on chemokines and adhesion molecules.


Immunology_Janeway

Immunology_Janeway. Migration of naive T cells into secondary lymphoid tissues depends on their binding to high endothelial venules (HEVs) through cell–cell interactions that are not antigen-specific but are governed by cell-adhesion molecules. The main classes of adhesion molecules involved in lymphocyte interactions are the selectins, the integrins, members of the immunoglobulin superfamily, and some mucin-like molecules (see Fig. 3.30). Entry of lymphocytes into lymph nodes occurs in distinct stages that include initial rolling of lymphocytes along the endothelial surface, activation of integrins, firm adhesion, and transmigration or diapedesis across the endothelial layer into the paracortical areas, the T-cell zones (Fig. 9.6). These stages are regulated by a coordinated interplay of adhesion molecules and chemokines that resembles the recruitment of leukocytes to sites of inflammation (see Chapter 3). Adhesion molecules have fairly broad roles in immune responses, being involved not only in


Immunology_Janeway

Immunology_Janeway. and chemokines that resembles the recruitment of leukocytes to sites of inflammation (see Chapter 3). Adhesion molecules have fairly broad roles in immune responses, being involved not only in lymphocyte migration but also in interactions between naive T cells and antigen-presenting cells (see Section 9-14).


Immunology_Janeway

Immunology_Janeway. The selectins (Fig. 9.7) are important for specifically guiding leukocytes to particular tissues, a phenomenon known as leukocyte homing. L-selectin (CD62L) is expressed on leukocytes, whereas P-selectin (CD62P) and E-selectin (CD62E) are expressed on vascular endothelium (see Section 3-18). L-selectin on naive T cells guides their exit from the blood into secondary lymphoid tissues by initiating a light attachment to the wall of the HEV that results in the T cells’ rolling along the endothelial surface (see Fig. 9.6). P-selectin and E-selectin are expressed on the vascular endothelium at sites of infection, and serve to recruit effector cells into the infected tissue. Selectins are cell-surface molecules with a common core structure and are distinguished from each other by the presence of different lectin-like domains in their extracellular portion. The lectin domains bind to particular sugar groups, and each selectin binds to a cell-surface carbohydrate. L-selectin binds to the


Immunology_Janeway

Immunology_Janeway. of different lectin-like domains in their extracellular portion. The lectin domains bind to particular sugar groups, and each selectin binds to a cell-surface carbohydrate. L-selectin binds to the carbohydrate moiety—sulfated sialyl-LewisX—of mucin-like molecules called vascular addressins, which are expressed on the surface of vascular endothelial cells. Two of these addressins, CD34 and GlyCAM-1 (see Fig. 9.7), are expressed on high endothelial venules in lymph nodes. A third, MAdCAM-1, is expressed on endothelium in mucosae, and guides lymphocyte entry into mucosal lymphoid tissue such as the Peyer’s patches in the gut.


Immunology_Janeway

Immunology_Janeway. The interaction between L-selectin and the vascular addressins is responsible for the specific homing of naive T cells to lymphoid organs. On its own, however, it does not enable the cell to cross the endothelial barrier into the lymphoid tissue. This requires the concerted action of chemokines and integrins. 9-6 Activation of integrins by chemokines is responsible for the entry of naive T cells into lymph nodes.


Immunology_Janeway

Immunology_Janeway. 9-6 Activation of integrins by chemokines is responsible for the entry of naive T cells into lymph nodes. Naive T cells rolling on the endothelium of HEVs via selectins require two additional types of cell-adhesion molecules to enter secondary lymphoid organs— integrins, and members of the immunoglobulin superfamily. Integrins bind tightly to their ligands after receiving signals that induce a change in their conformation. Signaling by chemokines activates integrins on leukocytes to bind tightly to the vascular wall in preparation for the migration of the leukocytes into sites of inflammation (see Section 3-18). Similarly, chemokines present at the luminal surface of the HEV activate integrins expressed on naive T cells during migration into lymphoid organs (see Fig. 9.6).


Immunology_Janeway

Immunology_Janeway. An integrin molecule consists of a large α chain that pairs noncovalently with a smaller β chain. There are several integrin subfamilies, broadly defined by their common β chains. We will be concerned here chiefly with the leukocyte integrins, which have a common β2 chain paired with distinct α chains (Fig. 9.8). All T cells express the integrin αL:β2 (CD11a:CD18), better known as leukocyte functional antigen-1 (LFA-1). It enables migration of both naive and effector T cells out of the blood. This integrin is also present on macrophages and neutrophils, and is involved in their recruitment to sites of infection (see Section 3-18). LFA-1 is also important in the adhesion of both naive and effector T cells to their target cells. Nevertheless, T-cell responses can be normal in individuals genetically lacking the β2 integrin chain and hence all β2 integrins,


Immunology_Janeway

Immunology_Janeway. Fig. 9.7 L-selectin binds to mucinlike vascular addressins. L-selectin is expressed on naive T cells and recognizes carbohydrate motifs. Its binding to sulfated sialyl-LewisX moieties on the vascular addressins Cd34 and GlyCaM-1 on hevs binds the lymphocyte weakly to the endothelium. The relative importance of Cd34 and GlyCaM-1 in this interaction is unclear. Cd34 has a transmembrane anchor and is expressed in appropriately glycosylated form only on hev cells, although it is found in other forms on other endothelial cells. GlyCaM-1 is expressed on hevs but has no transmembrane region and may be secreted into the hevs. The addressin MadCaM-1 is expressed on mucosal endothelium and guides lymphocytes to mucosal lymphoid tissue. The configuration shown represents mouse MadCaM-1, which contains an Iga-like domain closest to the cell membrane; human MadCaM-1 has an elongated mucin-like domain and lacks the Iga-like domain.


Immunology_Janeway

Immunology_Janeway. Fig. 9.8 Integrins are important in T-lymphocyte adhesion. Integrins are heterodimeric proteins containing a β chain, which defines the class of integrin, and an α chain, which defines the different integrins within a class. The α chain is larger than the β chain and contains binding sites for divalent cations that may be important in signaling. LFa-1 (integrin αL:β2) is expressed on all leukocytes. It binds ICaMs and is important in cell migration and in the interactions of T cells with antigen-presenting cells (apCs) or target cells; it is expressed at higher levels on effector T cells than on naive T cells. Lymphocyte peyer’s patch adhesion molecule (LpaM-1, or integrin α4:β7) is expressed by a subset of naive T cells and contributes to lymphocyte entry into mucosal lymphoid tissues by supporting adhesive interactions with vascular addressin MadCaM-1. vLa-4 (integrin α4:β1) is expressed strongly after T-cell activation. It binds to vCaM-1 on activated endothelium and is important


Immunology_Janeway

Immunology_Janeway. supporting adhesive interactions with vascular addressin MadCaM-1. vLa-4 (integrin α4:β1) is expressed strongly after T-cell activation. It binds to vCaM-1 on activated endothelium and is important for recruiting effector T cells into sites of infection.


Immunology_Janeway

Immunology_Janeway. Fig. 9.9 Immunoglobulin superfamily adhesion molecules involved in leukocyte interactions. adhesion molecules of the immunoglobulin superfamily bind to adhesion molecules of various types, including integrins (LFa-1 and vLa-4) and other immunoglobulin superfamily members [the Cd2–Cd58 (LFa-3) interaction]. These interactions have a role in lymphocyte migration, homing, and cell–cell interactions; see Fig. 3.24 for the other molecules listed here. including LFA-1. This is probably because T cells also express other adhesion molecules, including the immunoglobulin superfamily member CD2 and β1 integrins, which may compensate for the absence of LFA-1. Expression of the β1 integrins increases significantly at a late stage in T-cell activation, and they are thus often called VLAs, for very late activation antigens; they are important in directing effector T cells to inflamed target tissues.


Immunology_Janeway

Immunology_Janeway. At least five members of the immunoglobulin superfamily are especially important in T-cell activation (Fig. 9.9). Three very similar intercellular adhesion molecules (ICAMs)—ICAM-1, ICAM-2, and ICAM-3—all bind to the T-cell integrin LFA-1. ICAM-1 and ICAM-2 are expressed on endothelium as well as on antigen-presenting cells, and binding to these molecules enables lymphocytes to migrate through blood vessel walls. ICAM-3 is expressed only on naive T cells and is thought to have an important role in the adhesion of T cells to antigen-presenting cells by binding to LFA-1 expressed on dendritic cells. The two remaining immunoglobulin superfamily adhesion molecules, CD58 (formerly known as LFA-3) on the antigen-presenting cell and CD2 on the T cell, bind to each other; this interaction synergizes with that of ICAM-1 or ICAM-2 with LFA-1.


Immunology_Janeway

Immunology_Janeway. As discussed above in the context of lymphoid tissue development (see Section 9-3), naive T cells are specifically attracted into the T-cell zones of secondary lymphoid tissues by chemokines. The chemokines bind to proteoglycans in the extracellular matrix and high endothelial venule wall, forming a chemical gradient, and are recognized by receptors on the naive T cell. The extravasation of naive T cells is prompted by the chemokine CCL21, which is expressed by vascular high endothelial cells and the stromal cells of lymphoid tissues, as well as by dendritic cells that reside in T-cell zones. It binds to the chemokine receptor CCR7 on naive T cells, stimulating activation of the intracellular receptor-associated G-protein subunit Gαi. The resulting intracellular signaling rapidly increases the affinity of integrin binding (see Section 3-18).


Immunology_Janeway

Immunology_Janeway. Fig. 9.10 Lymphocytes in the blood enter lymphoid tissue by to the activation of LFa-1. This causes the T cell to bind tightly crossing the walls of high endothelial venules. The first step is to ICaM-1 on the endothelial cell, allowing migration across the the binding of L-selectin on the lymphocyte to sulfated carbohydrates endothelium. as in the case of neutrophil migration (see Fig. 3.31), (sulfated sialyl-LewisX) of GlyCaM-1 and Cd34 on the hev. Local matrix metalloproteinases on the lymphocyte surface (not shown) chemokines such as CCL21 bound to a proteoglycan matrix on the enable the lymphocyte to penetrate the basement membrane. hev surface stimulate chemokine receptors on the T cell, leading


Immunology_Janeway

Immunology_Janeway. The entry of a naive T cell into a lymph node is shown in detail in Fig. 9.10. Initial rolling of the T cell along the surface of HEVs is mediated by L-selectin. Recognition of CCL21 on the endothelial surface of the HEV by CCR7 on the T cell causes LFA-1 to become activated, increasing its affinity for ICAM-2 and ICAM-1. ICAM-2 is expressed constitutively on all endothelial cells, whereas in the absence of inflammation, ICAM-1 is expressed only on the high endothelial cells of secondary lymphoid tissues. The organization of LFA-1 molecules in the T-cell membrane is also altered by chemokine stimulation, such that they become concentrated in areas of cell–cell contact. This produces stronger binding, which arrests the T cell on the endothelial surface and thus enables it to enter the lymphoid tissue.


Immunology_Janeway

Immunology_Janeway. Once naive T cells have arrived in the T-cell zone via high endothelial venules, CCR7 directs their retention in this location, as they are attracted to dendritic cells that produce CCL21 and CCL19 in the T-cell zone. The naive T cells scan the surfaces of dendritic cells for specific peptide:MHC complexes, and if they find their antigen and bind to it, they are trapped in the lymph node. If they are not activated by antigen, naive T cells soon leave the lymph node (see Fig. 9.4). 9-7 The exit of T cells from lymph nodes is controlled by a chemotactic lipid.


Immunology_Janeway

Immunology_Janeway. 9-7 The exit of T cells from lymph nodes is controlled by a chemotactic lipid. T cells exit from a lymph node via the cortical sinuses, which lead into the medullary sinus and then the efferent lymphatic vessel. The egress of T cells from secondary lymphoid organs involves the lipid molecule sphingosine 1-phosphate (S1P) (Fig. 9.11). This lipid has chemotactic activity and signaling properties similar to those of chemokines, in that the receptors for S1P are G-protein-coupled receptors. A concentration gradient of S1P between the lymphoid tissues and lymph or blood acts to draw unactivated naive T cells expressing an S1P receptor away from the lymphoid tissues and back into circulation.


Immunology_Janeway

Immunology_Janeway. Fig. 9.11 The egress of lymphocytes from lymphoid tissue is mediated by a sphingosine 1-phosphate (S1P) gradient. The level of sphingosine 1-phosphate (s1p) within lymphoid tissue is low compared with efferent lymph, thereby forming an s1p gradient (indicated by shading). The s1p receptor 1 (s1pr1) expressed on naive T cells is responsive to the s1p gradient. In the absence of antigen recognition, s1pr1 signaling promotes T-cell egress from the T-cell zones into the efferent lymphatic vessel. T cells activated by an antigen-expressing dendritic cell upregulate Cd69, which causes a decrease in s1pr1 expression and retention in the T-cell zone. effector T cells eventually reexpress s1pr1 as Cd69 expression decreases, and thereby egress from the lymph node. FTY720 inhibits T-cell egression by downmodulating expression of s1pr1 by ligand-induced internalization and by s1pr1-mediated closure of egress ports on the endothelium by enhancement of junctional contacts (not shown).


Immunology_Janeway

Immunology_Janeway. T cells activated by antigen in lymphoid organs downregulate the surface expression of the S1P receptor, S1PR1, for several days. This loss of S1PR1 surface expression is caused by CD69, a surface protein whose expression is induced by T-cell receptor signaling and which acts to internalize S1PR1. During this period, T cells cannot respond to the S1P gradient and do not exit the lymphoid organ. After several days of proliferation, as T-cell activation wanes, CD69 expression decreases and S1PR1 reappears on the surface of effector T cells, allowing them to migrate out of the lymphoid tissue in response to the S1P gradient.


Immunology_Janeway

Immunology_Janeway. The regulation of the exit of both naive and effector lymphocytes from secondary lymphoid organs by S1P is the basis for a new kind of potential immunosuppressive drug, FTY720 (fingolimod). FTY720 inhibits immune responses by preventing lymphocytes from returning to the circulation, thereby sequestering them in lymphoid tissues and causing rapid onset of lymphopenia (a lack of lymphocytes in the blood). In vivo, FTY720 becomes phosphorylated and mimics S1P as an agonist at S1P receptors. Phosphorylated FTY720 may inhibit lymphocyte exit by effects on endothelial cells that increase tight junction formation and close exit portals, or by chronic activation of S1P receptors, leading to inactivation and downregulation of the receptor. 9-8 T-cell responses are initiated in secondary lymphoid organs by activated dendritic cells.


Immunology_Janeway

Immunology_Janeway. 9-8 T-cell responses are initiated in secondary lymphoid organs by activated dendritic cells. Secondary lymphoid organs were first shown to be important in the initiation of adaptive immune responses by ingenious experiments in which a flap of skin was isolated from the body wall so that it had blood circulation but no lymphatic drainage. Antigen placed in the flap did not elicit a T-cell response, showing that T cells do not become sensitized in the infected tissue itself. Rather, pathogens and their products must be transported to lymphoid tissues. Antigens introduced directly into the bloodstream are picked up by antigen-presenting cells in the spleen. Pathogens infecting other sites, such as a skin wound, are transported in lymph via lymphatic vessels and trapped in the lymph nodes nearest


Immunology_Janeway

Immunology_Janeway. Fig. 9.13 Antigen-presenting cells are distributed by type in specific areas of the lymph node. dendritic cells are found throughout the cortex of the lymph node in the T-cell areas. Mature dendritic cells are by far the strongest activators of naive T cells, and can present antigens from many types of pathogens, such as bacteria or viruses as shown here. Macrophages are distributed throughout the lymph node but are concentrated mainly in the marginal sinus, where the afferent lymph collects before percolating through the lymphoid tissue, and also in the medullary cords, where the efferent lymph collects before passing via the efferent lymphatics into the blood. B cells are found mainly in the follicles and can contribute to neutralizing soluble antigens such as toxins.


Immunology_Janeway

Immunology_Janeway. Dendritic cells can be activated via their TLRs and other pathogen-recognition receptors (see Chapter 3), by tissue damage, or by cytokines produced during the inflammatory response. Activated dendritic cells migrate to the lymph node and express the co-stimulatory molecules that are required, in addition to antigen, for the activation of naive T cells. In the lymphoid tissues, these dendritic cells present antigen to naive T lymphocytes and prime antigen-specific T cells to divide and mature into effector cells that reenter the circulation.


Immunology_Janeway

Immunology_Janeway. Macrophages, which are found in most tissues including lymphoid tissue, and B cells, which are located primarily in lymphoid tissue, can be similarly activated by pathogen-recognition receptors to express co-stimulatory molecules and act as antigen-presenting cells. The distribution of dendritic cells, macrophages, and B cells in a lymph node is shown schematically in Fig. 9.13. Only these three cell types express co-stimulatory molecules required to efficiently activate T cells, and they express these molecules only when activated in the context of infection. However, these cells activate T-cell responses in distinct ways. Dendritic cells take up, process, and present antigens from all types of sources, and are present mainly in the T-cell areas where they drive the initial clonal expansion and differentiation of naive T cells into effector T cells. By contrast, B cells and macrophages specialize in processing and presenting soluble antigens and antigens from intracellular pathogens,


Immunology_Janeway

Immunology_Janeway. and differentiation of naive T cells into effector T cells. By contrast, B cells and macrophages specialize in processing and presenting soluble antigens and antigens from intracellular pathogens, respectively; they interact mainly with effector CD4 T cells already primed by dendritic cells to recruit helper functions of those T cells.


Immunology_Janeway

Immunology_Janeway. 9-9 Dendritic cells process antigens from a wide array of pathogens. Dendritic cells primarily arise from myeloid progenitors within the bone marrow (see Fig. 1.3). They emerge from the bone marrow to migrate via the blood to tissues throughout the body, or directly to secondary lymphoid organs. There are two major classes of dendritic cells: conventional dendritic cells, and plasmacytoid dendritic cells (Fig. 9.14). The cell-surface markers and subset-specific transcription factors that distinguish these two classes, and the interferon-producing functions of plasmacytoid dendritic cells in the innate


Immunology_Janeway

Immunology_Janeway. Fig. 9.14 Conventional and plasmacytoid dendritic cells have different roles in the immune response. Mature conventional dendritic cells (left panel) are primarily concerned with the activation of naive T cells. There are several subsets of conventional dendritic cells, but these all process antigen efficiently, and when they are mature they express MhC proteins and co-stimulatory molecules for priming naive T cells. The cell-surface proteins expressed by the mature dendritic cell are described in the text. Immature dendritic cells lack many of the cell-surface molecules shown here but have numerous surface receptors that recognize pathogen molecules, including most of the Toll-like receptors (TLrs). plasmacytoid dendritic cells (right panel) are sentinels primarily for viral infections, and secrete large amounts of class I interferons. This category of dendritic cell is less efficient in priming naive T cells, but they express the intracellular receptors TLr-7 and TLr-9 for sensing


Immunology_Janeway

Immunology_Janeway. and secrete large amounts of class I interferons. This category of dendritic cell is less efficient in priming naive T cells, but they express the intracellular receptors TLr-7 and TLr-9 for sensing viral infections.


Immunology_Janeway

Immunology_Janeway. immune response, are discussed in Chapter 3. In this chapter we shall focus on the role of conventional dendritic cells in the adaptive immune response— presenting antigens to and activating naive T cells.


Immunology_Janeway

Immunology_Janeway. Conventional dendritic cells are abundant at barrier tissue sites, such as the intestines, lung, and skin, where they are in close contact with surface epithelia. They are also present in most solid organs such as the heart and kidneys. In the absence of infection or tissue injury, dendritic cells have low levels of co-stimulatory molecules, and so are not yet equipped to stimulate naive T cells. Like macrophages, dendritic cells are very active in ingesting antigens by phagocytosis using complement receptors and Fc receptors (which recognize the constant regions of antibodies in antigen:antibody complexes), and C-type lectins, which recognize carbohydrates and on dendritic cells include the mannose receptor, DEC 205, langerin, and Dectin-1. Other extracellular antigens are taken up nonspecifically by the process of macropinocytosis, in which large volumes of surrounding fluid are engulfed. In this way microbes that have evolved strategies to escape recognition by phagocytic


Immunology_Janeway

Immunology_Janeway. up nonspecifically by the process of macropinocytosis, in which large volumes of surrounding fluid are engulfed. In this way microbes that have evolved strategies to escape recognition by phagocytic receptors, such as bacteria with thick polysaccharide capsules, can be ingested. The versatility in pathways for antigen uptake enables dendritic cells to present antigens from virtually any type of microbe, including fungi, parasites, viruses, and bacteria (Fig. 9.15). Uptake of extracellular antigens by these pathways directs them into the endocytic pathway, where they are processed and presented on MHC class II molecules (see Chapter 6) for recognition by CD4 T cells.


Immunology_Janeway

Immunology_Janeway. A second route of antigen handling by dendritic cells occurs when antigen directly enters the cytosol, for example, through viral infection. Dendritic cells are directly susceptible to infection by some viruses, which enter the cytoplasm by binding to cell-surface molecules that act as entry receptors. Viral proteins synthesized in the cytoplasm of dendritic cells are processed in the proteasome and presented on the cell surface as peptides loaded onto MHC class I molecules after transport into the endoplasmic reticulum, as in any other type of virus-infected cell (see Chapter 6). This enables dendritic cells to present antigen to and activate naive CD8 T cells, which then differentiate into cytotoxic effector CD8 T cells that recognize and kill any virus-infected cell.


Immunology_Janeway

Immunology_Janeway. Fig. 9.15 The different routes by which dendritic cells can take presentation to Cd8 T cells (third panel). It is possible, however, for up, process, and present protein antigens. uptake of antigens exogenous antigens taken into the endocytic pathway to be delivered into the endocytic system, either by receptor-mediated phagocytosis into the cytosol for eventual delivery to MhC class I molecules for or by macropinocytosis, is considered to be the major route for presentation to Cd8 T cells, a process called cross-presentation delivering peptides to MhC class II molecules for presentation to (fourth panel). Finally, it seems that antigens can be transmitted from Cd4 T cells (first two panels). production of antigens in the cytosol, one dendritic cell to another, particularly for presentation to Cd8 for example, as a result of viral infection, is thought to be the T cells, although the details of this route are still unclear (fifth panel). major route for delivering peptides to MhC


Immunology_Janeway

Immunology_Janeway. to Cd8 for example, as a result of viral infection, is thought to be the T cells, although the details of this route are still unclear (fifth panel). major route for delivering peptides to MhC class I molecules for


Immunology_Janeway

Immunology_Janeway. Uptake of extracellular virus particles or virus-infected cells into the endocytic pathway by macropinocytosis or phagocytosis can also result in the presentation of viral peptides on MHC class I molecules. This phenomenon, known as cross-presentation, is an alternative to the usual cytosolic pathway for MHC class I antigen processing and is discussed in Section 6-5. Here, viral antigens that enter dendritic cells via endocytic or phagocytic vesicles may be diverted to the cytosol for proteasomal degradation and transferred to the endoplasmic reticulum for loading onto MHC class I molecules. The result is that viruses that do not directly infect dendritic cells can stimulate the activation of CD8 T cells. Cross-presentation is performed most efficiently by a subset of conventional dendritic cells that is specialized for stimulating T-cell responses to intracellular pathogens (see Section 6-5). Any viral infection can therefore lead to the generation of cytotoxic effector CD8 T cells,


Immunology_Janeway

Immunology_Janeway. cells that is specialized for stimulating T-cell responses to intracellular pathogens (see Section 6-5). Any viral infection can therefore lead to the generation of cytotoxic effector CD8 T cells, whether the virus can directly infect dendritic cells or not. In addition, viral peptides presented on the dendritic cell’s MHC class II molecules activate naive CD4 T cells, which leads to the production of effector CD4 T cells that stimulate the production of antiviral antibodies by B cells and produce cytokines that enhance the immune response.


Immunology_Janeway

Immunology_Janeway. In some cases, such as infections with herpes simplex or influenza viruses, the dendritic cells that migrate to the lymph nodes from peripheral tissues may not be the same cells that finally present antigen to naive T cells. In herpes simplex infection, for example, dendritic cells residing in the skin capture antigen and transport it to the draining lymph nodes (Fig. 9.16). There, some antigen is transferred to resident CD8α-positive dendritic cells, which are the dominant dendritic cells responsible for priming naive CD8 T cells in this infection.


Immunology_Janeway

Immunology_Janeway. Fig. 9.16 Langerhans cells take up antigen in the skin, migrate differentiate into mature dendritic cells that can no longer ingest to the peripheral lymphoid organs, and present foreign antigen but have co-stimulatory activity. now they can prime both antigens to T cells. Langerhans cells (yellow) are one type of naive Cd8 and Cd4 T cells. In the case of some viral infections, for immature dendritic cell that resides in the epidermis. They ingest example, with herpes simplex virus, some dendritic cells arriving from antigen in various ways but have no co-stimulatory activity (first the site of infection seem able to transfer antigen to resident dendritic panel). In the presence of infection, they take up antigen locally cells (orange) in the lymph nodes (third panel) for presentation of and then migrate to the lymph nodes (second panel). There they class I MhC-restricted antigens to naive Cd8 T cells (fourth panel).


Immunology_Janeway

Immunology_Janeway. This type of transfer means that antigens from viruses that infect but rapidly kill dendritic cells can still be presented by uninfected dendritic cells that have been activated via their TLRs and can take up the dying dendritic cells and cross-present this material. cells induces their migration to lymphoid organs and enhances antigen processing.


Immunology_Janeway

Immunology_Janeway. A critical step in the induction of adaptive immunity is the activation of dendritic cell maturation. When an infection occurs, dendritic cells capture pathogens by means of phagocytic receptors or macropinocytosis, and then activate responses to these pathogens through pattern recognition receptors such as TLRs (Fig. 9.17, top panel). Multiple members of the TLR family are expressed on tissue dendritic cells and are thought to be involved in detecting and signaling the presence of the various classes of pathogens (see Fig. 3.16). In humans, conventional dendritic cells express all known TLRs except for TLR-9, which is, however, expressed by plasmacytoid dendritic cells along with TLR-1 and TLR-7, and other TLRs to a lesser degree. In addition to the pattern recognition receptors described in Chapter 3, several of the phagocytic receptors used by dendritic cells to take up pathogens also provide maturation signals. Examples include the lectin DC-SIGN, which binds mannose and fucose


Immunology_Janeway

Immunology_Janeway. in Chapter 3, several of the phagocytic receptors used by dendritic cells to take up pathogens also provide maturation signals. Examples include the lectin DC-SIGN, which binds mannose and fucose residues present on a wide range of pathogens; and Dectin-1, which recognizes β-1,3-linked glucans found in fungal cell walls (see Fig. 3.2). Other receptors that can bind pathogens, such as receptors for complement, or phagocytic receptors such as the mannose receptor, may contribute to dendritic cell activation as well as to phagocytosis.


Immunology_Janeway

Immunology_Janeway. TLR signaling results in a significant alteration in the chemokine receptors expressed by dendritic cells, which facilitates their migration into secondary lymphoid tissues. This change in dendritic cell behavior is often called licensing, as the cells are now embarked on the program of differentiation that will enable them to activate T cells. TLR signaling induces expression of the receptor CCR7, which makes the activated dendritic cells sensitive to the chemokine CCL21 produced by lymphoid tissue and induces their migration through the lymphatics and into the local lymphoid tissues. Whereas T cells must cross the wall of high endothelial venules to leave the blood and reach the T-cell zones, dendritic cells entering via the afferent lymphatics migrate directly into the T-cell zones from the marginal sinus.


Immunology_Janeway

Immunology_Janeway. dendritic cells originate from bone marrow progenitors and migrate via the blood, from which they enter and populate most tissues, including peripheral lymphoid tissues, into which they can make direct entry. entry to particular tissues is based on the particular chemokine receptors they express: CCr1, CCr2, CCr5, CCr6, CXCr1, and CXCr2 (not all shown here, for simplicity). Tissue-resident dendritic cells are highly phagocytic via receptors such as dectin-1, deC 205, dC-sIGn, and langerin, and are actively macropinocytic, but they do not express co-stimulatory molecules. They carry most of the different types of Toll-like receptors (TLrs; see the text). at sites of infection, dendritic cells are exposed to pathogens, leading to activation of their TLrs (top panel). TLr signaling causes the dendritic cells to become activated (‘licensed’), which involves induction of the chemokine receptor CCr7 (second panel). TLr signaling also increases the processing of antigens taken up into