PPARgamma and TNF-alpha at the cross-roads of inflammation: Mechanisms of Immunoregulation and the Pathogenesis of Autoimmunity

Date of Completion

January 2011


Health Sciences, Immunology




The immune response is delicately balanced between allowing immune responses to infections while preventing responses to self-tissue. We have investigated the role the transcription factor PPARγ and the cytokine TNF-α play in this immunoregulatory balance. TNF-α is involved in driving inflammation and blockade of TNF-α is effective at ameliorating many autoimmune diseases. However, in some cases blocking TNF-α can exacerbate or even initiate autoimmunity, suggesting an anti-inflammatory role for TNF-α. We have discovered a novel effect of TNF-α in augmenting the suppressive function of thymically derived regulatory T cells (Tregs). Tregs that cannot express the type 2 TNF receptor (TNFR2) are unable to suppress a T cell-mediated model of colitis, suggesting that TNF-α signaling through TNFR2 is required for Treg suppressive function in vivo. ^ We have also determined that TGF-β induced Tregs do not require TNFR2 for suppressive function, thereby functionally differentiating thymically derived from peripherally derived Tregs. In addition to our studies on TNF-α, we have also investigated the role of the nuclear hormone receptor PPARγ in immunoregulation. PPARγ is expressed in many immune cells including dendritic cells (DCs), macrophages, Tregs, and conventional T cells. Activation of PPARγ down-regulates immune responses by suppressing cytokine production and proliferation, decreasing co-stimulation on antigen-presenting cells, and enhancing Treg function. We have discovered novel functions of PPARγ in both DCs and T cells. In DCs, we find that PPARγ drives the synthesis of the vitamin A metabolite retinoic acid. This enhances the conversion of T cells into suppressive Tregs. As such, this may be one mechanism by which PPARγ ligands exert immunosuppressive effects and are effective at treating autoimmune diseases. In contrast to the immunoregulatory effects mediated by DCs, we also find that PPARγ is required for CD4 T cell-mediated autoimmunity under conditions of lymphopenia. PPARγ knockout CD4 T cells are unable to mediate disease in murine models of graft-versus-host disease and colitis. Mechanistically, we find that PPARγ is required for the survival and proliferation of CD4 T cells during lymphopenia. These results demonstrate that PPARγ and TNF-α hold critical places in the immunoregulatory balance by driving context-dependant pro and anti-inflammatory effects. ^