November 1, 2010

The Origins of Autoimmunity-Causing T Cells

Microscope image of red, green and blue cells in a mouse spleen Immune cells in the mouse spleen, a site of Th17 development. Helper T cells are in green.Lane and McConnell, courtesy of Wellcome Images.


Autoimmune diseases arise when the immune system, which normally protects the body from invading microbes, mistakenly attacks the body’s own tissues. These diseases include type 1 diabetes, psoriasis and multiple sclerosis. The immune system employs many different types of cells to regulate disease. A better understanding of the complex signals between these cells will help researchers design better ways to prevent and treat autoimmune diseases.

T cells play a major role in the immune system. They can be divided into 2 categories: cytotoxic, which kill infected cells directly, and helper, which make proteins called cytokines that instruct other cells to make certain molecules, move to a specific location or develop in a particular way. Depending on which cytokines are present as a T cell matures, it can become one of many types of helper T cell, each of which has a distinct role in immunity.

A team led by Dr. John O’Shea of NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) set out to investigate the development of Th17 cells. These helper T cells make a cytokine called IL-17 that causes inflammation. While helpful for fighting infections, Th17 cells have also been linked with several autoimmune disorders.

Past studies have found that a combination of 3 cytokines—interleukin-1-beta (IL-1-beta), interleukin-6 (IL-6) and transforming growth factor beta (TGF-beta)—drive Th17 cell development. However, TGF-beta also drives the development of other T cells (regulatory T cells) that dampen the inflammatory response and help prevent autoimmunity.

To further explore Th17 development, the scientists exposed immature mouse T cells to a variety of cytokines in culture. As reported in the October 21, 2010, issue of Nature, replacing TGF-beta with another cytokine, IL-23, worked just as well. Gene expression analysis found that Th17 cells from TGF-beta cultures had higher levels of an anti-inflammatory cytokine called IL-10. In contrast, Th17 cells developed with IL-23 showed higher levels of IL-18R1 and T-bet—2 molecules known to be involved in the development of experimental autoimmune encephalomyelitis (EAE), a mouse disease that resembles human multiple sclerosis.

The researchers next looked at the ability of both sets of Th17 cells to cause autoimmune disease. They transferred the cells into mice engineered to lack mature T cells of their own. Mice that received Th17 cells from IL-23 cultures showed more severe symptoms of EAE. This shows that Th17 cells behave differently depending on which cytokines drove their development, with IL-23 producing Th17 cells that are more likely to cause autoimmune disease.

These findings shed light on Th17 development, revealing 2 kinds of Th17 cells with distinct functions. The discovery of IL-23 as a driving force in Th17 development points to potential new targets for therapies against autoimmunity.

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