SMAD regulatory networks construct a balanced immune system

Immunology. 2013 May;139(1):1-10. doi: 10.1111/imm.12076.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Autocrine Communication / immunology
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Humans
  • Immune Tolerance / physiology
  • Immunity, Mucosal / physiology*
  • Immunoglobulin A / immunology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology*
  • Mice
  • Paracrine Communication / immunology
  • Smad Proteins / immunology*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / cytology
  • Th17 Cells / immunology*
  • Transforming Growth Factor beta / immunology


  • Immunoglobulin A
  • Smad Proteins
  • Transforming Growth Factor beta