Peroxisome proliferator-activated receptor gamma is required for CD4+ T cell-mediated lymphopenia-associated autoimmunity.

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) was shown to play an immunoregulatory role in many immune-related cell types, and activation of PPAR gamma was reported to be an effective therapeutic approach in murine and human autoimmune disease. However, despite an association between lymphopenia and autoimmunity, there has been no study on the role of T cell PPAR gamma in lymphopenia-associated autoimmunity. In the present studies, we examined the role of PPAR gamma in CD4(+) T cells in two murine models of lymphopenia-associated autoimmunity. Surprisingly, we found that PPAR gamma expression in CD4(+) CD25(-) T cells (T effector cells [Teffs]) is actually required for development of autoimmunity under lymphopenic conditions. Mechanistically, the inability of PPAR gamma-deficient (T-PPAR) Teffs to mediate lymphopenic autoimmunity is associated with a significant decrease in accumulation of Teffs in the spleen, lymph nodes, and tissues after adoptive transfer. This abnormal accumulation of T-PPAR Teffs was associated with defects in both in vivo proliferation and survival. Additionally, T-PPAR Teffs demonstrated decreased cytokine production in inflammatory sites and decreased expression of the homing receptor alpha 4 beta 7. Finally, these abnormalities in T-PPAR Teff function were not elicited by lymphopenia alone but also required the additional activation involved in the mediation of autoimmunity. Thus, in contrast to its documented immunosuppressive role, we identified an unexpected function for PPAR gamma in Teffs: a role in Teff proliferation and survival in lymphopenia-associated autoimmunity. These findings highlight both the multifunctional role of PPAR gamma in T cells and the complexity of PPAR gamma as a potential therapeutic target in autoimmunity. The Journal of Immunology, 2011, 187: 4161-4169.