Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis.
Peroxisome proliferator-activated receptor (PPAR) gamma activation has been implicated in the prevention of immunoinflammatory disorders; however, the mechanisms of regulation of effector and regulatory CD4+ T cell functions by endogenously activated PPAR-gamma remain unclear. We have used PPAR-gamma-deficient CD4+ T cells obtained from tissue-specific PPAR-gamma null mice (i.e., PPAR-gamma fl/fl; MMTV-Cre+) to investigate the role of endogenous PPAR-gamma on regulatory T cell (Treg) and effector CD4+ T cell function. Overall, we show that the loss of PPAR-gamma results in enhanced Ag-specific proliferation and overproduction of IFN-gamma in response to IL-12. These findings correlate in vivo with enhanced susceptibility of tissue-specific PPAR-gamma null mice to trinitrobenzene sulfonic acid-induced colitis. Furthermore, the transfer of purified PPAR-gamma null CD4+ T cells into SCID recipients results in enteric disease. To test the assertion that the deficiency of PPAR-gamma in Treg impairs their ability to prevent effector T cell-induced colitis, we performed cotransfer studies. These studies demonstrate that PPAR-gamma-expressing, but not PPAR-gamma null Treg, prevent colitis induced by transfer of naive CD4+ T cells into SCID recipients. In line with these findings, the production of IFN-gamma by spleen and mesenteric lymph node-derived CD4+ T cells was down-regulated following transfer of PPAR-gamma-expressing, but not PPAR-gamma null, Treg. In conclusion, our data suggest that endogenous PPAR-gamma activation represents a Treg intrinsic mechanism of down-regulation of effector CD4+ T cell function and prevention of colitis.
Hontecillas
Raquel
R
Laboratory of Nutritional Immunology and Molecular Nutrition, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. magarzo@vt.edu
Bassaganya-Riera
Josep
J
D000818:Animals; D000941:Antigens / Q000276:immunology; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015536:Down-Regulation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009928:Organ Specificity / Q000276:immunology; D047495:PPAR gamma / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation
D000941:Antigens; D047495:PPAR gamma; D018664:Interleukin-12; D007371:Interferon-gamma