PPARγ is required for CD4+ T cell proliferation, survival, and disease-mediation in lymphopenia-associated autoimmunity. (101.21)

Abstract

Ligands for the nuclear hormone receptor PPARγ ameliorate many autoimmune conditions in both mice and humans. Recent reports have also suggested that PPARγ is important in regulatory T cell function and in preventing the development of pathogenic Th17 cells. In contrast to this role of PPARγ in suppressing autoimmunity, we now find that CD4+ T cell PPARγ expression is required for development of autoimmunity under lymphopenic conditions. PPARγ-deficient (PPARγ-/-) CD4+ T cells are unable to mediate disease in both murine graft-versus-host disease and an adoptive transfer model of colitis. In the colitis model, PPARγ is required for the accumulation and cytokine production of CD4+ T cells in the spleen, mesenteric lymph nodes, and colonic lamina propria. This defect is specific for CD4+ T cells as PPARγ-/- CD8+ T cells accumulate equally to wild type CD8+ T cells. Mechanistically, PPARγ-/- CD4+ T cells show diminished in vivo proliferation as assessed via Ki67 staining, but no difference in activation marker expression demonstrating that PPARγ is required for proliferation and cytokine production but not for activation. Endogenous PPARγ-/- CD4+ T cells recover normally after mice are sub-lethally irradiated demonstrating that loss of proliferative potential requires antigen-induced activation as well as lymphopenia. Our results identify a novel function for PPARγ in the proliferation and survival of CD4+ T cells in lymphopenia-associated autoimmunity.