1. The transcriptional regulator Sin3A balances IL‐17A and Foxp3 expression in primary CD4 T cells.
- Author
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Perucho, Laura, Icardi, Laura, Di Simone, Elisabetta, Basso, Veronica, Agresti, Alessandra, Vilas Zornoza, Amaia, Lozano, Teresa, Prosper, Felipe, Lasarte, Juan José, and Mondino, Anna
- Abstract
The Sin3 transcriptional regulator homolog A (Sin3A) is the core member of a multiprotein chromatin‐modifying complex. Its inactivation at the CD4/CD8 double‐negative stage halts further thymocyte development. Among various functions, Sin3A regulates STAT3 transcriptional activity, central to the differentiation of Th17 cells active in inflammatory disorders and opportunistic infections. To further investigate the consequences of conditional Sin3A inactivation in more mature precursors and post‐thymic T cell, we have generated CD4‐Cre and CD4‐CreERT2 Sin3AF/F mice. Sin3A inactivation in vivo hinders both thymocyte development and peripheral T‐cell survival. In vitro, in Th17 skewing conditions, Sin3A‐deficient cells proliferate and acquire memory markers and yet fail to properly upregulate Il17a, Il23r, and Il22. Instead, IL‐2+ and FOXP3+ are mostly enriched for, and their inhibition partially rescues IL‐17A+ T cells. Notably, Sin3A deletion also causes an enrichment of genes implicated in the mTORC1 signaling pathway, overt STAT3 activation, and aberrant cytoplasmic RORγt accumulation. Thus, together our data unveil a previously unappreciated role for Sin3A in shaping critical signaling events central to the acquisition of immunoregulatory T‐cell phenotypes. Synopsis: This study identifies a role for the transcriptional regulator Sin3A in shaping Th‐17 differentiation. Inducible Sin3A deletion causes overt STAT3 activation and aberrant cytoplasmic RORγt localization hindering IL‐17A levels in favor of Foxp3 expression.The transcriptional regulator Sin3A contributes to CD4 T‐cell development and differentiation.Sin3A inactivation in mature T cells promotes mTORC1 signaling, STAT3 activation, and aberrant cytoplasmic RORγt accumulation.Sin3A balances IL‐17A, IL‐2, and Foxp3, thereby shaping the immunoregulatory potential of Th17 lymphocytes. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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