A Critical Role for Transcription Factor Smad4 in T Cell Function that Is Independent of Transforming Growth Factor β Receptor Signaling

Abstract

Summary Transforming growth factor-beta (TGF-β) suppresses T cell function to maintain self-tolerance and to promote tumor immune evasion. Yet how Smad4, a transcription factor component of TGF-β signaling, regulates T cell function remains unclear. Here we have demonstrated an essential role for Smad4 in promoting T cell function during autoimmunity and anti-tumor immunity. Smad4 deletion rescued the lethal autoimmunity resulting from transforming growth factor-beta receptor (TGF-βR) deletion and compromised T-cell-mediated tumor rejection. While Smad4 was dispensable for T cell generation, homeostasis and effector function, it was essential for T cell proliferation following activation in vitro and in vivo. The transcription factor Myc was identified to mediate Smad4-controlled T cell proliferation. This study thus reveals a requirement of Smad4 for T-cell-mediated autoimmunity and tumor rejection, which is beyond the current paradigm. It highlights a TGF-βR-independent role for Smad4 in promoting T cell function, autoimmunity and anti-tumor immunity.

Functions of Smad Transcription Factors in TGF-β1–Induced Selectin Ligand Expression on Murine CD4 Th Cells

“…Cre + Smad2-fl/fl Smad3-fl/fl mice were always used before 6 wk of age, a time point at which in our hands mice exhibited no signs of disease. No such disease was ever noted in mice with Smad4 deleted in T cells, consistent with previous reports (22,23). Mice of both sexes were used throughout these experiments, and no differences between sexes were noted.…”

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

“…Moreover, absence of TGF-β signaling did not greatly impact antiviral cytokine secretion by D b :GP 33-41 LCMV-specific CD8 T cells upon cognate peptide stimulation (Supplemental Figure 1D). We also found that TGF-β signaling only minimally suppressed the effector markers KLRG and Ly6C on virus-specific CD8 T cells, or granzyme B on IFN-γ-producing cells, after GP [33][34][35][36][37][38][39][40][41] peptide stimulation (Supplemental Figure 1, E-G). Overall, these data show that deletion of Tgfbr2 prior to infection only minimally affected CD8 T cell antiviral responses early after chronic LCMV infection.…”

“…A recent study demonstrated that CD4 T cellspecific deletion of SMAD4 during development using Cd4-Cre mice reduces accumulation of activated CD4 and CD8 T cells due to reduced c-myc induction and compromises transgenic OT-II CD4 T cell-based B16-OVA melanoma rejection (35). In addition, KLRG + effector CD8 T cell differentiation, but not cell numbers, was defective in SMAD4-deficient OT-1 transgenic T cells after lung influenza-OVA infection (58).…”

The effect of perioperative analgesic drugs omnopon and dexketoprofen on the functional activity of immune cells in murine model of tumor surgery

“…As a pleiotropic cytokine, TGF-β regulates various immune cell types including natural killer cells, myeloid cells, CD4+ and CD8+ T cells, promotes generation of T-regulatory cells. These properties are essential for the maintenance of tissue homeostasis and self-tolerance, but are also involved in tumor immune evasion mechanisms [13]. Surgical trauma, pain and blood loss were shown to induce the increase of systemic levels of TGF-β [8].…”