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

Abstract

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

PPAR-γ agonist rosiglitazone protects peritoneal membrane from dialysis fluid-induced damage

“…PPAR-g agonists have anti-inflammatory properties and these drugs are capable of downregulating most cells in the innate and adaptive immune system, [22][23][24][25] and of activating a regulatory T-cell response. 26,27 Our data demonstrate that administration of RSG enhances the recruitment of leukocytes to the peritoneal cavity of PD fluid-instilled mice. The increase in cell influx is significant for both CD4 þ and CD8 þ T-cells but not for B-lymphocytes or macrophages.…”

“…1,2 Exposing the peritoneum to PD fluids induces inflammation and a local diabetic environment, associated with the generation AGEs and the structural and functional deterioration of the peritoneal membrane. 9 PPAR-g agonists have both anti-diabetic and anti-inflammatory properties [20][21][22][23][24][25][26][27] and they have been associated with anti-fibrotic effects in several experimental models and in patients. [28][29][30][31][32] However, the potential of PPAR-g agonists to act as therapeutic agents to ameliorate peritoneal membrane damage, as well as their mechanisms of action, have not yet been explored in depth.…”

“…20,21 Besides their glucose-lowering effects, PPAR-g agonists also have anti-inflammatory properties by modulating both innate and adaptive immune responses and by activating a regulatory T-cell response. [22][23][24][25][26][27] Probably as a consequence of these multiple anti-inflammatory actions, PPAR-g ligands have demonstrated anti-fibrotic effects in several experimental models, including diabetic and nondiabetic chronic kidney diseases. [28][29][30][31] It has been described that PPAR-g agonists improve renal function in patients with incipient diabetic nephropathy.…”

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

“…Different colitis animal models, including dextran sulfate sodium (DSS)-induced colitis and adoptive CD4 + CD25 -CD45RB high Tcell transfer into RAG -/-mice, have indicated that PPARγ agonists can inhibit inflammatory bowl disease (IBD). Moreover, PPARγ deficiency in T cells led to increased disease susceptibility and severity (Hontecillas and Bassaganya-Riera, 2007). PPARγ null CD4 + T cells from MMTV-Cre/PPARγ fl/fl mice proliferate following a recall response to ovalbumin (OVA) in OVA-immunized mice and produce IFN-γ upon TCR stimulation with increased disease susceptibility to IBD (Hontecillas and Bassaganya-Riera, 2007).…”

“…Moreover, PPARγ deficiency in T cells led to increased disease susceptibility and severity (Hontecillas and Bassaganya-Riera, 2007). PPARγ null CD4 + T cells from MMTV-Cre/PPARγ fl/fl mice proliferate following a recall response to ovalbumin (OVA) in OVA-immunized mice and produce IFN-γ upon TCR stimulation with increased disease susceptibility to IBD (Hontecillas and Bassaganya-Riera, 2007). PPARγ deficiency leads to decreased numbers of CD4 + Foxp3 + T cells and increased CD4 + IFN-γ + cells, suggesting that PPARγ plays a role in regulatory T-cell (Treg) survival and regulation of effector T-cell functions.…”