Autocrine Transforming Growth Factor-β1 Promotes In Vivo Th17 Cell Differentiation

Abstract

Summary TGFβ1 is a regulatory cytokine that has an important role in controlling T cell differentiation. T cell-produced TGFβ1 acts on T cells to promote Th17 cell differentiation and the development of experimental autoimmune encephalomyelitis (EAE). However, the exact TGFβ1-producing T cell subset required for Th17 cell generation and its cellular mechanism of action remain unknown. Here we showed that deletion of the Tgfb1 gene from activated T cells and Treg cells, but not Treg cells alone, abrogated Th17 cell differentiation resulting in almost complete protection from EAE. Furthermore, differentiation of T cells both in vitro and in vivo demonstrated that TGFβ1 was highly expressed by Th17 cells and acted in a predominantly autocrine manner to maintain Th17 cells in vivo. These findings reveal an essential role for activated T cell-produced TGFβ1 in promoting the differentiation of Th17 cells and controlling inflammatory diseases.

Generation of Th17 cells in response to intranasal infection requires TGF-β1 from dendritic cells and IL-6 from CD301b + dendritic cells

“…Ablation of TGF-β1 production by CD11c + cells, however, did not completely inhibit S. pyogenes-induced Th17 formation, indicating that other cells of hematopoietic origin are involved. CD4 + T cells, perhaps regulatory T cells, were good candidates based on work in the EAE model (17). Nonetheless, S. pyogenes p:MHCII-specific naive CD4 + T cells did not become Foxp3 + regulatory T cells during S. pyogenes inoculation, and we found no role for TGF-β1 production by CD4 + T cells in S. pyogenes-driven Th17 differentiation.…”

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…TGF-b also regulates Th17-cell differentiation (Bettelli et al 2006;Veldhoen et al 2006a;Li et al 2007;Manel et al 2008;Yang et al 2008;Gutcher et al 2011). Th17 cells express the lineage-specific transcription factor RAR (retinoic acid receptor)-related orphan receptor C (RORC) in humans (and RORgt in mice) and produce many cytokines, including IL-17A, IL-17F, IL-21, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Ivanov et al 2006;Korn et al 2009).…”

“…However, despite the indication that autocrine TGF-b signaling promotes TGF-b production in DCs, whether DCs represent the critical source of TGF-b for pTreg-cell differentiation, as proposed (Kashiwagi et al 2015), remains to be validated by genetic methods, for example, using CD11c-Cre-mediated deletion of floxed Tgfb1. Indeed, it has been shown that T cells themselves are the essential source of TGF-b for Th17 differentiation Gutcher et al 2011). …”

“…CD4 þ T cells that express a dnTbRII do not differentiate into Th17 cells, and mice expressing a dnTbRII under the control of the CD4 promoter are resistant to EAE, indicating that TGF-b signaling is critical for the in vivo generation of pathogenic Th17 cells and EAE development (Veldhoen et al 2006b). Furthermore, genetic studies show that autocrine TGF-b signaling is required for in vivo Th17 differentiation, as mice with T-cell-specific deletion of Tgfb1 do not develop Th17 cells and are resistant to EAE Gutcher et al 2011). In contrast, cell-culture studies suggest that treatment of CD4 þ T cells with TGFb1 produces nonpathogenic Th17 cells that fail to induce EAE (McGeachy et al 2007;Ghoreschi et al 2010), whereas treatment with TGF-b3 induces a pathogenic Th17 population that causes disease (Lee et al 2012).…”

The role of Th17 and Treg responses in the pathogenesis of RSV infection

“…Together, they induce RORγt, the characteristic transcription factor of the Th17 lineage, in a STAT3-dependent manner (9,46). Moreover, in the presence of IL-6, Th17 cells can secrete TGF-β in an autocrine manner thus contributing to a stable and maintained Th17 response (67). The absolute requirement for TGF-β is attributable to the inhibition of Th1 cell differentiation, since Th1 cells strongly inhibit Th17 differentiation in the absence of TGF-β (62).…”