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.
Highlights
Regulatory T (Treg) cells are a heterogeneous subset of helper T cells that express the forkhead box transcription factor Foxp3 and play an essential role in the maintenance of peripheral tolerance and suppression of excessive immune responses [1,2,3,4,5]
Our findings strongly suggest that autocrine TGF-β1 inhibits trans-differentiation of Treg cells into Th1 cells by down-regulating the expression of IL-12Rβ
In line with these studies, we found that the frequency of Treg cells in the thymus was increased in T cell-specific TGF-β1-deficient mice
Summary
Regulatory T (Treg) cells are a heterogeneous subset of helper T cells that express the forkhead box transcription factor Foxp and play an essential role in the maintenance of peripheral tolerance and suppression of excessive immune responses [1,2,3,4,5]. By using Foxp3+ cell-specific TGF-β1-deficient mice, it was shown that TGF-β1 from Treg cells is required for the suppression of type 1 helper T (Th1)-dependent intestinal inflammation [23,24], whereas TGF-βRII signaling in Treg cells is required for Treg cell suppression of Th17 immune responses in the colon [25]. We demonstrate that autocrine TGF-β1 plays little role in the development of thymic Treg cells and that TGF-β1-deficient Treg cells exhibit a slightly diminished suppressive activity in vitro. Mechanistic studies showed that TGF-β1-deficient Treg cells are less resistant to become IFN-γ-producers upon IL-12, but not IL-27, stimulation, and that autocrine TGF-β1 is required for suppression of Il12rb expression in Treg cells. Our findings provide a crucial role for autocrine TGF-β1 in maintaining the stability and function of Treg cells
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