UMass Chan Medical School Faculty Publications


SMAD regulatory networks construct a balanced immune system

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Department of Pathology

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


Immunity | Immunology and Infectious Disease


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-beta (TGF-beta), whose deficiency results in spontaneous systemic autoimmunity in mice. The dominant function of TGF-beta 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-beta, 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-beta 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-beta in the gut that are dictacted by fluid orchestrations of SMADs and their myriad partners.

DOI of Published Version



Immunology. 2013 May;139(1):1-10. doi: 10.1111/imm.12076. Link to article on publisher's site

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