As shown in Figure 6, the suppressive activity of Treg

cells in MLN from sirolimus-treated mice was obviously stronger in comparison with that of PBS-treated mice. The data in this study clearly indicate that the significant immunosuppressive capacities of sirolimus, an inhibitor of mTOR, in TNBS-induced colitis resulted from a prominent increase of the functional activity of CD4+ CD25+ Obeticholic Acid Treg cells. The observed enhancement of the potency of Treg cells might additionally be the result of a differential down-regulation of pro-inflammatory signals of DC subsequently favouring the education of Treg cells. Furthermore, the beneficial effect of sirolimus was also involved in down-regulation of IL-17-producing T lymphocyte (Th17) response in the perpetuation of click here intestinal inflammation. Recent compelling evidence demonstrated that Th17 cells play a crucial role in the induction of autoimmune diseases.[11, 34] On the contrary, Treg cells actively restrain the inflammatory response, suppress development of autoimmune diseases and dampen a wide spectrum of immune responses.[8, 9] The differentiation of naive Th cells into Th17 or Treg cells is mainly driven by cytokine milieu. For example, TGF-β is a critical differentiation factor for the generation of Treg cells[35] and also directs FoxP3 expression, which is a specific marker in Treg cells

and is responsible for the function of these cells.[36] On the other hand, TGF-β, acting together with IL-6, induces the differentiation of pathogenic Th17 cells from naive T cells.[37] In addition, Th cell differentiation is manipulated by distinct transcription factors. For example, STAT5 and FOXP3 direct Treg 3-mercaptopyruvate sulfurtransferase cell differentiation and induce the production of regulatory cytokines such as TGF-β and IL-10,[38] and signal transducer and activator of transcription 3 (STAT3) and RORγt dominate

Th17 cell formation and IL-17 production.[39] Furthermore, the critical role of Th cell-intrinsic mTOR signalling, which regulates the differentiation between effector and Treg cells, has been well characterized.[40] Inhibition of mTOR can modulate the expression of FoxP3, IL-17 and RORγt genes directly, which contribute to induction of FoxP3 and suppression of Th17 polarization.[41] By inhibiting the mTOR signalling, sirolimus has been reported to promote Treg cell differentiation, proliferation and distribution[42] and suppress the formation of Th17 cells.[43] However, in inflammatory responses such as IBD, the role of mTOR inhibition in regulating Th17 and Treg cell differentiation has not been explored thoroughly. Here, we found that in the progression of TNBS-induced colitis, treatment with sirolimus, the inhibitor of mTOR, led to a significant increase in the percentage of CD4+ CD25+ Foxp3+ T cells in MLN and spleen (data not shown).