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

Transforming growth factor beta 1 (TGF-beta 1) is an immunosuppresive cytokine that plays an essential role in immune homeostasis. It is well known that regulatory T (Treg) cells express TGF-beta 1; however, the role of autocrine TGF-beta 1 in the development, function, and stability of Treg cells remains poorly understood. We found that Treg cell-derived TGF-beta 1 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 naive 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-beta 1-deficient mice, which was associated with increased frequency of IFN-gamma-producers among Treg cells. TGF-beta 1-deficient Treg cells were more prone to express IFN-gamma than TGF-beta 1-sufficient Treg cells in a dendritic cell-mediated stimulation in vitro as well as in an adoptive transfer study in vivo. Mechanistically, TGF-beta 1-deficient Treg cells expressed higher levels of Il12rb2 and were more sensitive to IL-12-induced conversion into IFN-gamma-producing Treg cells or IFN-gamma-producing exTreg cells than TGF-beta 1-sufficient Treg cells. Our findings demonstrate that autocrine TGF-beta 1 plays a critical role in the optimal suppressive activity and stability of Treg cells by downregulating IL-12R on Treg cells.