A critical role for transcription factor Smad4 in T cell function that is independent of transforming growth factor β receptor signaling.

Abstract

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. Although Smad4 was dispensable for T cell generation, homeostasis, and effector function, it was essential for T cell proliferation after 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.

• Authors: Ai-Di Gu, Song Zhang, Yunqi Wang, Hui Xiong, Thomas A Curtis, Yisong Y Wan
• Journal: Immunity (Immunity) Vol. 42 Issue 1 Pg. 68-79 (Jan 20 2015) ISSN: 1097-4180 [Electronic] United States
• PMID: 25577439 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Myc protein, mouse
• Proto-Oncogene Proteins c-myc
• Receptors, Transforming Growth Factor beta
• Smad4 Protein

Topics

• Animals
• Autoimmunity (genetics)
• Cell Proliferation (genetics)
• Cells, Cultured
• Graft vs Host Disease (immunology)
• Immune Tolerance (genetics)
• Lymphocyte Activation (genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Proto-Oncogene Proteins c-myc (metabolism)
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Signal Transduction (genetics, immunology)
• Smad4 Protein (genetics, metabolism)
• T-Lymphocyte Subsets (physiology, transplantation)
• T-Lymphocytes, Regulatory (physiology, transplantation)
• Transplantation Chimera
• Tumor Escape