A novel role for peroxisome proliferator-activated receptor alpha in T cell physiology

Lipids and lipid metabolism have a number of regulatory effects on immune and inflammatory responses. The nuclear hormone receptor PPARα, a transcription factor that can be activated by various lipid species, is important in regulating various aspects of inflammation. This dissertation demonstrates that PPARα also plays an active role in regulating host adaptive immune responses. PPARα is expressed by a number of cells in the immune system, including T and B lymphocytes. The PPARα that is expressed in lymphocytes is transactivation and transrepression competent, both processes being important for its regulation of lymphocyte function.; Expression of PPARα in CD4+ T cells regulates the expression and production of IL-2 and IFN-γ following activation of these cells. The regulation of cytokine production by PPARα is mediated, in part, through its ability to regulate the expression of T-bet. PPARα regulates T-bet through a novel IFN-γ independent signaling mechanism that does not require DNA binding or ligand activation of the nuclear hormone receptor. PPARα was subsequently found to suppress T-bet expression in activated CD4+ T cells through its ability to inhibit the activation of p38 MAP kinase.; Additional studies in this dissertation demonstrate that the temporal regulation of activated CD4+ T cells by PPARα is important for the development of normal humoral immune responses. PPARα−/− mice immunized with foreign protein antigens produced markedly lower levels of antigen-specific antibodies when compared to identically immunized PPARα+/+ mice. Polyclonal activation of B cells in vitro and immunization of PPARα−/− and PPARα+/+ mice with T-cell independent antigens demonstrated that antibody production by B lymphocytes is not directly affected by the expression of PPARα in these cells. Adoptive transfer of PPARα+/+ B cells and PPARα+/+ CD4+ T cells into Rag2−/− mice produced good titers of antigen-specific antibodies following immunization with a T-cell dependent antigen. Conversely, identically immunized Rag2−/− mice reconstituted with PPARα+/+ B cells and PPARα−/− CD4+ T cells were severely compromised in their ability to generate antigen-specific antibodies. From the findings presented in this dissertation, it is proposed that PPARα expression in CD4+ T cells is important in the generation of humoral immune responses to foreign protein antigens.