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

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‐CreER T2 Sin3A F / 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.

MicroRNAs -122 and -1247 restrain the pathogenicity of effector CD4+ T cells in autoimmune inflammation

“…Moreover, IL-18 has been reported to play a similar role to IL-1β in the promotion of IL-17 production and autoimmunity 44 . Finally, Sap130 function remains more enigmatic, but it is known to associate with Sin3A ( 45 ), which is essential for IL-17 production 46 . Collectively, the identification of these 3 direct targets provide new biological context to miR-122-5p-mediated regulation of Th17 cells.…”

Histone and Histone Acetylation-Related Alterations of Gene Expression in Uninvolved Psoriatic Skin and Their Effects on Cell Proliferation, Differentiation, and Immune Responses

“…Among the complex components, SIN3A showed abnormal expression in uninvolved skin (Figure 1). Sin3A regulated T cell development [138], in particular Th17 cell differentiation, and the establishment of their inflammatory potential [139]. While in the skin, the same molecule is known to regulate terminal differentiation and the maintenance of epidermis homeostasis [140] (Figure 5B).…”