Th17 cells and Tregs: unlikely allies

Abstract

Identification of CD4⁺Foxp3⁺ T_regs and Th17 modified the historical Th1-Th2 paradigm. Currently, the Th17-T_regs dichotomy provides a dominant conceptual framework for the comprehension of immunity/inflammation and tolerance/immunosuppression in an increasing number of diseases. Targeting proinflammatory Th17 cells or immunosuppressive T_regs has been widely considered as a promising therapeutic strategy in the treatment of major human diseases, including autoimmunity and cancer. The efficacy and safety of such therapy rely on a thorough understanding of immunobiology and interaction of these two subsets of Th cells. In this article, we review recent progress concerning complicated interplay of Th17 cells and T_regs There is compelling evidence that T_regs potently inhibit Th1 and Th2 responses; however, the inhibitory effect of T_regs on Th17 responses is a controversial subject. There is increasing evidence showing that T_regs actually promote the differentiation of Th17 cells in vitro and in vivo and consequently, enhanced the functional consequences of Th17 cells, including the protective effect in host defense, as well as detrimental effect in inflammation and in the support of tumor growth. On the other hand, Th17 cells were also the most potent Th subset in the stimulation and support of expansion and phenotypic stability of T_regs in vivo. These results indicate that these two subsets of Th cells reciprocally stimulate each other. This bidirectional crosstalk is largely dependent on the TNF-TNFR2 pathway. These mutual stimulatory effects should be considered in devising future Th17 cell- and T_reg-targeting therapy.

Keywords: Foxp3; IL-17; TNF; TNFR2; immunosuppression; inflammation.

Figure 1.. Reciprocal stimulation of T_regs and Th17 cells.

T_regs are able to promote the differentiation and function of Th17 cells, through a mechanism involving the supply of TGF-β, which is required for Th17 differentiation, or inhibition of Th1 and Th2 cytokines and IL-2, which are known to block Th17 differentiation. Induced and natural Th17 cells also stimulate the activation and expansion and promote Foxp3 expression of T_regs by producing TNF, IL-2, or other mediators required for the survival and activation of T_regs. Therefore, the immunosuppressive T_regs and proinflammatory Th17 cells reciprocally stimulate and temper each other, resulting in a dynamic equilibrium in an ongoing immune/inflammatory response.