Although Th17 cells help battle bacteria and viruses, they can also turn traitor and promote autoimmune attacks. Klotz et al. report a possible new way to stall development of these self-targeting cells.

Studies have implicated Th17cells in several autoimmune diseases, including multiple sclerosis. The master switch for Th17 differentiation is the transcription factor RORγt, but researchers know little about how cells control RORγt activity. Klotz et al. homed in on one possible regulator, the nuclear receptor PPARγ, whose immune tasks range from quelling inflammation to inhibiting proliferation of T cells.

Mice lacking PPARγ in their T cells developed severe EAE—the rodent equivalent of MS—more rapidly than did mice with normal T cells. Mice with PPARγ-deficient T cells also harbored about three times as many autoreactive Th17 cells in the central nervous system. Stimulating PPARγ with the synthetic molecule PIO ameliorated disease symptoms. In cultured T cells, the same treatment reduced RORγt expression.

These results suggest that PPARγ hampers the differentiation of Th17 cells in mice. The receptor does the same in humans, as naive human T cells stimulated with PPARγ agonists produced less IL-17 in culture. PPARγ exerts its effects, the team discovered, by preventing the SMRT repressor from leaving the RORγt promoter in response to the Th17-promoting cytokines IL-6 and TGF-β.

PPARγ is selective—it had no effect on differentiation of other cell types such as regulatory T cells or Th1 and Th2 T cells. That Th17 cells can be restrained without hobbling other immune cells is good news for potential PPARγ-activating treatments. However, the authors caution that PPARγ only soothed EAE symptoms, rather than eliminating the disease. They are now trying to pin down naturally occurring PPARγ triggers and determine whether any of them malfunction during autoimmune diseases. Although the α and δ isoforms of PPAR also dampen EAE, they seem to have more of an effect on IFN-γ–producing Th1 cells than on Th17 cells, but what governs this specificity is not yet known.