The Role Of TGF-β In Stabilizing Human Natural Regulatory T Cells Under Inflammatory Conditions

Regulatory T cell is an important subpopulation of T cells with immunosuppressive function. The present focus is thymus-derived natural CD4+ CD25+ regulatory T cell with the feature of Foxp3 expression. Regulatory T cell has an important role in peripheral immune suppression including maintaining the body’s internal environment stability, preventing autoimmune diseases, tumor immune escape and regulation of transplant rejection. Whereas the population of Regulatory T cell in peripheral blood is not abundant, moreover, it may be unstable in some specific inflammatory environments. Thus the first step for its clinical application is to get a large number of Tregs with high purity, strong immunosuppressive ability and stability in inflammatory environments.The common method for nTregs expansion in vitro is to use interleukin-2 (IL-2) and anti-CD3/CD28 monoclonal antibody as co-stimulating signal, and rapamycin is added in order to improve the purity of nTregs.TGF-P is a cytokine regulating cell growth and differentiation, playing an important role in inducing CD4+ T cell to iTreg,but the function of TGF-β to nTreg is not clear.We added low concentration of TGF-β during the nTreg culture and discovered that the addition of TGF-P enhanced nTreg’s purity of amplification and suppressive function. What’s more important, in inflammatory condition such as IL-1β and IL-6, nTregs pretreated with TGF-β avoided transforming to IL-17-secreting cells and maintained Foxp3 expression. TGF-β has an positive effect of maintaining Tregs stability in inflammatory environments.Our study suggests that the influence of TGF-β on nTreg secreting IL-17 may work through two aspects. One aspect is the HLA-DR up-regulation in the nTregs pretreated with TGF-β.The other aspect is related to STAT3 expression and phosphorylation. For the latter one, we suggest that STAT3 supresses IL-17 expression through an unclassical approach or the inhibition of STAT3 influences TGF-β signal in nTreg. Thus in STAT3-inhibited nTregs,the function of TGF-β is neutralized and the IL-17-secreting cells increase.