SMAD regulatory networks construct a balanced immune system

A balanced immune response requires combating infectious assaults while striving to maintain quiescence towards the self. One of the central players in this process is the pleiotropic cytokine transforming growth factor‐β (TGF‐β), whose deficiency results in spontaneous systemic autoimmunity in mice. The dominant function of TGF‐β is to regulate the peripheral immune homeostasis, particularly in the microbe‐rich and antigen‐rich environment of the gut. To maintain intestinal integrity, the epithelial cells, myeloid cells and lymphocytes that inhabit the gut secrete TGF‐β, which acts in both paracrine and autocrine fashions to activate its signal transducers, the SMAD transcription factors. The SMAD pathway regulates the production of IgA by B cells, maintains the protective mucosal barrier and promotes the balanced differentiation of CD4+ T cells into inflammatory T helper type 17 cells and suppressive FOXP3+ T regulatory cells. While encounters with pathogenic microbes activate SMAD proteins to evoke a protective inflammatory immune response, SMAD activation and synergism with immunoregulatory factors such as the vitamin A metabolite retinoic acid enforce immunosuppression toward commensal microbes and innocuous food antigens. Such complementary context‐dependent functions of TGF‐β are achieved by the co‐operation of SMAD proteins with distinct dominant transcription activators and accessory chromatin modifiers. This review highlights recent advances in unravelling the molecular basis for the multi‐faceted functions of TGF‐β in the gut that are dictacted by fluid orchestrations of SMADs and their myriad partners.