TGF‐β1 signaling and Smad7 control T‐cell responses in health and immune‐mediated disorders

Abstract

Transforming growth factor (TGF)‐β1, a member of the TGF‐β superfamily, is produced by many immune and non‐immune cells and has pleiotropic effects on both innate and adaptive immunity, especially in the control of T cell differentiation and function. Consistently, loss of TGF‐β1 function is associated with exacerbated T cell‐dependent inflammatory responses that culminate in pathological processes in allergic and immune‐mediated diseases. In this review, we highlight the roles of TGF‐β1 in immunity, focusing mainly on its ability to promote differentiation of regulatory T cells, T helper (Th)‐17, and Th9 cells, thus contributing to amplifying or restricting T cell responses in health and human diseases (e.g. inflammatory bowel diseases, type I diabetes, asthma, and multiple sclerosis), In addition, we discuss the involvement of Smad7, an inhibitor of TGF‐β1 signaling, in immune‐mediated disorders (e.g. psoriasis, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel diseases), as well as the discordant results of clinical trials with mongersen, an oral pharmaceutical compound containing a Smad7 antisense oligonucleotide, in patients with Crohn's disease. Further work is needed to ascertain the reasons for such a discrepancy as well as to identify better candidates for treatment with Smad7 inhibitors.This article is protected by copyright. All rights reserved

Regulation of Treg cells by cytokine signaling and co-stimulatory molecules

“…SMAD6 −/− mice can develop a variety of cardiovascular diseases ( 43 ). SMAD7 inhibits the formation of SMAD complexes and prevents the phosphorylation of SMAD2 and SMAD3, thereby interrupting the signaling cascade and influencing TGF-β signaling and Treg induction ( Figure 1 ) ( 44 ).…”

Type I and II interferons, transcription factors and major histocompatibility complexes were enhanced by knocking down the PRRSV-induced transforming growth factor beta in monocytes co-cultured with peripheral blood lymphocytes

“…In mice, TGFβ has been found to down-regulate CD14 expression in lipopolysaccharide (LPS)-stimulated macrophages, leading to the suppression of the MyD88-dependent signaling pathway ( 38 , 39 ). Moreover, TGFβ has been shown to suppress MHCII, IL-12p40, and CD40 expressions in murine macrophages ( 38 ), Th1 cell differentiation, Th1-mediated inflammatory response, and the expressions of IFNγ, IL-2, and IL-4 ( 40 ) as well as the activation of macrophages, dendritic cells (DCs), and natural killer cells ( 38 ). In contrast, TGFβ promotes Tregs differentiation through the up-regulation of Smad3 and Foxp3 expressions ( 41 ).…”