Abstract
The Mads/Mef2 (Mef2a/b/c/d) family of transcription factors (TFs) regulates differentiation of muscle cells, neurons and hematopoietic cells. By functioning in physiological feedback loops, Mef2 TFs promote the transcription of their repressor, Hdac9, thereby providing temporal control of Mef2-driven differentiation. Disruption of this feedback is associated with the development of various pathologic states, including cancer. Beside their direct involvement in oncogenesis, Mef2 TFs indirectly control tumor progression by regulating antitumor immunity. We recently reported that in CD4+CD25+Foxp3+ T-regulatory (Treg) cells, Mef2d is required for the acquisition of an effector Treg (eTreg) phenotype and for the activation of an epigenetic program that suppresses the anti-tumor immune responses of conventional T and B cells. We now report that as with Mef2d, the deletion of Mef2c in Tregs switches off the expression of Il10 and Icos and leads to enhanced antitumor immunity in syngeneic models of lung cancer. Mechanistically, Mef2c does not directly bind the regulatory elements of Icos and Il10, but its loss-of-function in Tregs induces the expression of the transcriptional repressor, Hdac9. As a consequence, Mef2d, the more abundant member of the Mef2 family, is converted by Hdac9 into a transcriptional repressor on these loci. This leads to the impairment of Treg suppressive properties in vivo and to enhanced anti-cancer immunity. These data further highlight the central role played by the Mef2/Hdac9 axis in the regulation of CD4+Foxp3+ Treg function and adds a new level of complexity to the analysis and study of Treg biology.
Highlights
The role played by Treg cells in restraining anti-tumor immunity [1] and in limiting transplant rejection [2] is well established and has made the study of Treg differentiation, stability, subpopulations and homeostasis a major focus of immunology [3]
Foxp3 is the master transcription factor (TF) involved in sustaining Treg suppressive identity and mutations leading to Foxp3 loss-of-function are associated clinically with the severe autoimmunity that presents as IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) [4,5,6]
Despite its low expression in murine Tregs (Figure 1A), we deleted Mef2c expression in Foxp3+ Treg cells by crossing Mef2cfl/fl mice and Foxp3YFP/Cre mice so as to investigate the existence of alternative, supplementary or redundant transcriptional programs with respect to those controlled by Mef2d, its more abundant paralogue
Summary
The role played by Treg cells in restraining anti-tumor immunity [1] and in limiting transplant rejection [2] is well established and has made the study of Treg differentiation, stability, subpopulations and homeostasis a major focus of immunology [3]. We recently identified Mef2d as a TF that supports and integrates the transcriptional responses of Foxp, allowing Tregs to acquire the phenotype of effector Tregs (eTregs) [18]. The dynamic nature of Mef protein complexes has been little investigated in T effector cells and is completely unexplored in Treg cell. By exploring the roles of Mef2c in CD4+ Foxp3+ Treg cells, we discovered the existence of a feed-back circuit involving Mef2c, Mef2d and Hdac. By exploring the roles of Mef2c in CD4+ Foxp3+ Treg cells, we discovered the existence of a feed-back circuit involving Mef2c, Mef2d and Hdac9 Interference in this circuit decreases the immunosuppressive properties of Foxp3+ Tregs in vivo. Our results stress the need to deepen the study of this signaling pathway so as to more fully understand the transcriptional dynamics of Treg cells
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