Detalle Publicación

The transcriptional regulator Sin3A balances IL-17A and Foxp3 expression in primary CD4 T cells

Autores: Perucho, L.; Icardi, L.; Di Simone, E.; Basso, V.; Agresti, A.; Vilas Zornoza, Amaia; Lozano Moreda, Teresa; Prosper Cardoso, Felipe; Lasarte Sagastibelza, Juan José; Mondino, A. (Autor de correspondencia)
Título de la revista: EMBO REPORTS
ISSN: 1469-221X
Volumen: 24
Número: 5
Páginas: e55326
Fecha de publicación: 2023
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 ROR¿t 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.