Peroxisome Proliferator-Activated Receptor γ Is Required for CD4+ T Cell-Mediated Lymphopenia-Associated Autoimmunity

Abstract

The nuclear hormone receptor PPARγ has been shown to play an immuno-regulatory role in many immune-related cell types and activation of PPARγ has been reported to be an effective therapeutic approach in murine and human autoimmune disease. However, despite an association between lymphopenia and autoimmunity, there have been no prior studies of the role of T cell PPARγ in lymphopenia-associated autoimmunity. In the present studies we examined the role of PPARγ in CD4+ T cells in two murine models of lymphopenia-associated autoimmunity. Surprisingly, we find that PPARγ expression in CD4+ CD25− T cells (Teff) is actually required for development of autoimmunity under lymphopenic conditions. Mechanistically, the inability of PPARγ-deficient (T-PPAR) Teff to mediate lymphopenic autoimmunity is associated with a significant decrease in accumulation of Teff in the spleen, lymph nodes and tissues after adoptive transfer. This abnormal accumulation of T-PPAR Teff is associated with defects in both in vivo proliferation and survival. Additionally, T-PPAR Teff demonstrate decreased cytokine production in inflammatory sites and decreased expression of the homing receptor α4β7. 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 now identify an unexpected function for PPARγ in Teff, namely a role in Teff proliferation and survival in lymphopenia-associated autoimmunity. These findings highlight both the multifunctional role of PPARγ in T cells and the complexity of PPARγ as a potential therapeutic target in autoimmunity.

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

“…Recent studies have more precisely analyzed the function of PPARγ in CD4 T-cell-targeted PPARγ-deficient mice. Expression of IL-7Rα, which is important for survival and homeostatic proliferation, in PPARγ-deficient CD4 + T cells was slightly diminished in a lymphopenic autoimmunity model, possibly suggesting a prosurvival effect in T cells (Housley et al, 2011).…”

Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells

“…Other groups showed a critical role for PPARγ in naturally occurring regulatory T cells (nTreg) and adipose tissue resident Treg cell function29. Despite the many anti-inflammatory effects of PPARγ, Pparg deficient CD4 + T cells lack the ability to induce systemic autoimmunity following adoptive transfer into a lymphopenic host30. Therefore, the overall biological significance of PPARγ in T-cell function is controversial, and the role of PPARγ in the regulation of fatty acid metabolism in CD4 + T cells is unknown.…”

Gender-specific differences in PPARγ regulation of follicular helper T cell responses with estrogen

“…One recent paper reported that PPARγ is required for the development of autoimmunity in lymphopenic conditions due to increased apoptosis with reduced IL-7Rα expression of CD4-PPARγ KO T cells19, while there is a controversial result from previous studies showing that PPARγ is a negative regulator of T cell activation. It was reported that the transfer of PPARγ-deficient effector T cells into RAG-knockout mice showed a robust induction of colitis17.…”