Novel role for peroxisome proliferator-activated receptor alpha in T cell physioloogy

Lipids and lipid metabolism have a number of regulatory effects on immune and inflammatory responses. The nuclear hormone receptor PPAR?, a transcription factor that can be activated by various lipid species, is important in regulating various aspects of inflammation. This dissertation demonstrates that PPAR? also plays an active role in regulating host adaptive immune responses. PPAR? is expressed by a number of cells in the immune system, including T and B lymphocytes. The PPAR? that is expressed in lymphocytes is transactivation and transrepression competent, both processes being important for its regulation of lymphocyte function. Expression of PPAR? in CD4+ T cells regulates the expression and production of IL-2 and IFN-gamma following activation of these cells. The regulation of cytokine production by PPAR? is mediated, in part, through its ability to regulate the expression of T-bet. PPAR? regulates T-bet through a novel IFN-? independent signaling mechanism that does not require DNA binding or ligand activation of the nuclear hormone receptor. PPAR? 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 PPAR? is important for the development of normal humoral immune responses. PPAR?-/- mice immunized with foreign protein antigens produced markedly lower levels of antigen-specific antibodies when compared to identically immunized PPAR?;+/+ mice. Polyclonal activation of B cells <italic>in vitro