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Peroxisome Proliferator-Activated Receptor Is Required for Regulatory CD4⁺ T Cell-Mediated Protection against Colitis

Laboratory of Nutritional Immunology and Molecular Nutrition, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061

Peroxisome proliferator-activated receptor (PPAR) 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- remain unclear. We have used PPAR--deficient CD4⁺ T cells obtained from tissue-specific PPAR- null mice (i.e., PPAR- fl/fl; MMTV-Cre⁺) to investigate the role of endogenous PPAR- on regulatory T cell (Treg) and effector CD4⁺ T cell function. Overall, we show that the loss of PPAR- results in enhanced Ag-specific proliferation and overproduction of IFN- in response to IL-12. These findings correlate in vivo with enhanced susceptibility of tissue-specific PPAR- null mice to trinitrobenzene sulfonic acid-induced colitis. Furthermore, the transfer of purified PPAR- null CD4⁺ T cells into SCID recipients results in enteric disease. To test the assertion that the deficiency of PPAR- in Treg impairs their ability to prevent effector T cell-induced colitis, we performed cotransfer studies. These studies demonstrate that PPAR--expressing, but not PPAR- null Treg, prevent colitis induced by transfer of naive CD4⁺ T cells into SCID recipients. In line with these findings, the production of IFN- by spleen and mesenteric lymph node-derived CD4⁺ T cells was down-regulated following transfer of PPAR--expressing, but not PPAR- null, Treg. In conclusion, our data suggest that endogenous PPAR- activation represents a Treg intrinsic mechanism of down-regulation of effector CD4⁺ T cell function and prevention of colitis.

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¹ Address correspondence and reprint requests to Dr. Raquel Hontecillas or Dr. Josep Bassaganya-Riera, Laboratory of Nutritional Immunology and Molecular Nutrition, 253 Wallace Hall, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061. E-mail addresses: rmagarzo{at}vt.edu and jbassaga{at}vt.edu

² Abbreviations used in this paper: IBD, inflammatory bowel disease; PPAR-, peroxisome proliferator-activated receptor ; TZD, thiazolidinedione; Treg, regulatory T cell; TNBS, trinitrobenzene sulfonic acid; MLN, mesenteric lymph node; LPL, lamina propria leukocytes; DSS, dextran sodium sulfate; Teff, effector T cells.

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