B cells drive auto-T cells to the brain

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Science Immunology  05 Oct 2018:
Vol. 3, Issue 28, eaav4512
DOI: 10.1126/sciimmunol.aav4512


Self-reactive T cells that traffic to the brain tissue of patients with multiple sclerosis are driven by antigen-experienced B cells.

Neurologists and immunologists have long held onto the concept that multiple sclerosis (MS) is a T cell–mediated autoimmune disease. In the past, the idea that B cells played an important role was often viewed with some skepticism. Support for this point of view may have been based on the enduring absence of a validated MS autoantibody. However, the remarkable effectiveness of B cell depletion therapy was a major breakthrough for patients and served to illuminate the importance of B cells in MS immunopathology. Yet, the mechanistic details that describe how B cells make substantial contributions in MS remain unclear. To gain more understanding Jelcic and co-authors investigated how B cells influence the T cells that populate the MS brain.

MS-derived T cells are known to have increased rates of spontaneous proliferation in the absence of exogenous stimuli or antigen; this is termed autoproliferation. The factors driving this autoproliferation and its relationship to MS pathology remain unclear. The authors linked this phenomenon to several disease-relevant factors, including increased autoproliferation during remission and in patients carrying the human leukocyte antigen (HLA)–DR15 haplotype—a genetic risk factor for MS. Interestingly, the authors identified memory B cells as key drivers of T cell autoproliferation through HLA-dependent mechanisms and consequently observed reduced autoproliferation following B cell depletion therapy. Characterizing autoproliferating T cells suggested that these cells are capable of brain-homing, as these classical and nonclassical T helper 1 (TH1) cells express chemokine receptors important for brain entry. The authors then confirmed via T cell receptor sequencing that autoproliferating clones present in the periphery are enriched in brain lesions. These results support the concept that B cells are essential players in driving autoreactive and potentially pathogenic T cell responses in MS, which is of substantial interest, given the striking efficacy of B cell–depleting therapies.

Although this study provides an important new paradigm for understanding B cells in MS, the work also generates many important questions regarding B cells and autoproliferating T cells, including understanding the elevated autoproliferation during remission and the specificity of the activating B cells.

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