TGF-β1 inhibition of IFN-γ-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent

Abstract

In addition to classic Smad signaling pathways, the pleiotropic immunoregulatory cytokine TGF-β1 can activate MAP kinases, but a role for TGF-β1-MAP kinase pathways in T cells has not been defined heretofore. We have shown previously that TGF-β1 inhibits Th1 development by inhibiting IFN-γ's induction of T-bet and other Th1 differentiation genes, and that TGF-β1 inhibits receptorproximal IFN-γ-Jak-Stat signaling responses. We now show that these effects of TGF-β1 are independent of the canonical TGF-β1 signaling module Smad3, but involve a specific MAP kinase pathway. In primary T cells, TGF-β1 activated the MEK/ERK and p38 MAP kinase pathways, but not the JNK pathway. Inhibition of the MEK/ERK pathway completely eliminated the inhibitory effects of TGF-β1 on IFN-γ responses in T cells, whereas inhibition of the p38 pathway had no effect. Thus, TGF-β1's inhibition of IFN-γ signaling in T cells is mediated through a highly specific Smad3-independent, MEK/ERK-dependent signaling pathway.

Phase I Trial of TGF-β2 Antisense GM-CSF Gene-Modified Autologous Tumor Cell (TAG) Vaccine

“…This heterotetrameric receptor complex is then able to suppress DC and helper T-cell function through regulation of the Smad complex and non-Smad MAP (mitogen-activated protein) kinases (12,18). Polak et al recently showed that tumor-infiltrating, tolerogenic DCs and suppressor T-cell lymphocytes in malignant melanoma correlate with immunosuppressive TGF-b1, TGF-b2, and IL-10 expression (15).…”

“…9) which, rather than cross-priming CD8 þ cytotoxic T cells, inhibit T-effector antitumor activities (9)(10)(11) in part through TGFb-dependent suppression of antigen-presenting dendritic cell (DC) processes (12). Further, both tumor-infiltrating, tolerogenic DCs and suppressor T lymphocytes express the TGF-b receptor 1 (TGF-bR1) and are therefore susceptible to immunosuppressive modulations by TGF-b1 and TGFb2 produced by tumor cells (13)(14)(15)(16)(17)(18). Circulating Th1-suppressive cytokines, including TGF-b and IL-10, that are frequently elevated in patients with advanced cancer mediate immune suppression in tumor-bearing animal models by downregulating antigen recognition, Th1 activation, and antitumor immune effector functions (19)(20)(21).…”

Coronin 1A is an essential regulator of the TGFβ receptor/SMAD3 signaling pathway in Th17 CD4+ T cells

“…This alteration correlated with impaired SMAD3 activation and could explain the emergence of aberrant IFNg þ cells among Coro1a À/À Th17 CD4 þ T cells. Accordingly, Takimoto et al reported that the TGFb-mediated suppression of IFNg was partially impaired in both Smad2 À/À T cells and in Smad3 À/À T cells, and fully abrogated in the double knockout T cells [52,53]. Furthermore, it has been shown that Th17 cell population is heterogeneous.…”

TGF-β receptor maintains CD4 T helper cell identity during chronic viral infections

“…This was surprising in that TGF-β has been shown to restrict Th1 cells' TBET and IFN-γ secretion in other contexts (54,55). However, these molecules seem sufficiently suppressed during chronic infection, even in the absence of TGF-β signaling.…”