Autocrine TGF-β1 Maintains the Stability of Foxp3+ Regulatory T Cells via IL-12Rβ2 Downregulation

Abstract

Transforming growth factor beta 1 (TGF-β1) is an immunosuppresive cytokine that plays an essential role in immune homeostasis. It is well known that regulatory T (Treg) cells express TGF-β1; however, the role of autocrine TGF-β1 in the development, function, and stability of Treg cells remains poorly understood. We found that Treg cell-derived TGF-β1 was not required for the development of thymic Treg cells in mice, but played a role in the expression of latency-associated peptide and optimal suppression of naïve T cell proliferation in vitro. Moreover, the frequency of Treg cells was significantly reduced in the mesenteric lymph nodes of the Treg cell-specific TGF-β1-deficient mice, which was associated with increased frequency of IFN-γ-producers among Treg cells. TGF-β1-deficient Treg cells were more prone to express IFN-γ than TGF-β1-sufficient Treg cells in a dendritic cell-mediated stimulation in vitro as well as in an adoptive transfer study in vivo. Mechanistically, TGF-β1-deficient Treg cells expressed higher levels of Il12rb2 and were more sensitive to IL-12-induced conversion into IFN-γ-producing Treg cells or IFN-γ-producing exTreg cells than TGF-β1-sufficient Treg cells. Our findings demonstrate that autocrine TGF-β1 plays a critical role in the optimal suppressive activity and stability of Treg cells by downregulating IL-12R on Treg cells.

GARP as a Therapeutic Target for the Modulation of Regulatory T Cells in Cancer and Autoimmunity

“…TGF-β is a pleiotropic cytokine, that is an important mediator during the development of Treg and the maintenance of their immunoregulatory state ( 25 ). Besides Treg, TGF-β is expressed by a multitude of cell types and tissues and participates in the mediation of numerous pathways, including development, wound healing, homeostasis, and cancer ( 26 ).…”

Progesterone modulates CD4+CD25+FoxP3+ regulatory T Cells and TGF‐β1 in the maternal‐fetal interface of the late pregnant mouse

“…TGF-β1 is essential for the generation and function of nTreg. 47,48 The addition of TGF-β1 enhances the conversion rate of naive CD4 + T cells into Tregs in the periphery.TGF-β1 secreted by Tregs is partially responsible for maintaining immunosuppressive functions. 8,49 Our experiment also found that the expressions of TGF-β1 mRNA and protein in decidua basalis were increased after progesterone administration.…”

“…Treg cells can secrete TGF‐β1. TGF‐β1 is essential for the generation and function of nTreg 47,48 . The addition of TGF‐β1 enhances the conversion rate of naive CD4 + T cells into Tregs in the periphery.TGF‐β1 secreted by Tregs is partially responsible for maintaining immunosuppressive functions 8,49 .…”

Tregs in Autoimmunity: Insights Into Intrinsic Brake Mechanism Driving Pathogenesis and Immune Homeostasis

“…The downstream molecules such as Smad3 and STAT5 of TGF-β and IL-2 signaling pathways, respectively, play a critical role for Treg generation and Foxp3 stability via binding to conserved non-coding sequences (CNS) in the Foxp3 gene locus ( 35 ). TGF-β signaling also supports Treg stability by prevention of conversion into IFN-γ-expressing cells through inhibition of IL-12R expression ( 36 ). These results indicated that IL-2 and TGF-β are pivotal in Treg homeostasis in preventing autoimmunity.…”