Dataset Information

A Biological Circuit Involving Mef2c, Mef2d, and Hdac9 Controls the Immunosuppressive Functions of CD4+Foxp3+ T-Regulatory Cells.

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.

SUBMITTER: Di Giorgio E

PROVIDER: S-EPMC8287581 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ObjectiveThe approximately 45-cM insulin-dependent diabetes 9 (Idd9) region on mouse chromosome 4 harbors several different type 1 diabetes-associated loci. Nonobese diabetic (NOD) mice congenic for the Idd9 region of C57BL/10 (B10) mice, carrying antidiabetogenic alleles in three different Idd9 subregions (Idd9.1, Idd9.2, and Idd9.3), are strongly resistant to type 1 diabetes. However, the mechanisms remain unclear. This study aimed to define mechanisms underlying the type 1 diabetes resistance afforded by B10 Idd9.1, Idd9.2, and/or Idd9.3.Research design and methodsWe used a reductionist approach that involves comparing the fate of a type 1 diabetes-relevant autoreactive CD8(+) T-cell population, specific for residues 206-214 of islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP(206-214)), in noncongenic versus B10 Idd9-congenic (Idd9.1 + Idd9.2 + Idd9.3, Idd9.2 + Idd9.3, Idd9.1, Idd9.2, and Idd9.3) T-cell receptor (TCR)-transgenic (8.3) NOD mice.ResultsMost of the protective effect of Idd9 against 8.3-CD8(+) T-cell-enhanced type 1 diabetes was mediated by Idd9.1. Although Idd9.2 and Idd9.3 afforded some protection, the effects were small and did not enhance the greater protective effect of Idd9.1. B10 Idd9.1 afforded type 1 diabetes resistance without impairing the developmental biology or intrinsic diabetogenic potential of autoreactive CD8(+) T-cells. Studies in T- and B-cell-deficient 8.3-NOD.B10 Idd9.1 mice revealed that this antidiabetogenic effect was mediated by endogenous, nontransgenic T-cells in a B-cell-independent manner. Consistent with this, B10 Idd9.1 increased the suppressive function and antidiabetogenic activity of the FoxP3(+)CD4(+)CD25(+) T-cell subset in both TCR-transgenic and nontransgenic mice.ConclusionsA gene(s) within Idd9.1 regulates the development and function of FoxP3(+)CD4(+)CD25(+) regulatory T-cells and, in turn, the activation of CD8(+) effector T-cells in the pancreatic draining lymph nodes, without affecting their development or intrinsic diabetogenic potential.

Dataset Information

A Biological Circuit Involving Mef2c, Mef2d, and Hdac9 Controls the Immunosuppressive Functions of CD4+Foxp3+ T-Regulatory Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets