Get started
Work

A cell-intrinsic steroidogenesis and sensing circuit maintains homeostatic Th17 cell state 3383

Year: 2025
Type: article
Abstract: Description CD4+ IL-17-producing T (Th17) cells are heterogenous; homeostatic Th17 (Th17Hom) maintain homeostatic tissue functions and inflammatory Th17 (Th17Inf) drive pathogenic autoimmune tissue inflammation. While IL-23 has a recognized role in driving Th17Inf, the pathways that preserve Th17 cells in a homeostatic state have remained enigmatic. Our study reveals that endogenous glucocorticoid (GC) production downstream of Cyp11a1, a key enzyme for steroid hormone production, distinguishes Th17Hom from Th17Inf. TCR signaling initiates Cyp11a1 expression, which is amplified and maintained co-operatively by TGFβ1 and IL-6, cytokines pivotal for Th17Hom differentiation. Additionally, Th17Hom exhibit heightened GC sensitivity compared to Th17Inf, providing additional context for the reported steroid resistance of Th17 cells. Cyp11a1 and the glucocorticoid receptor (GR) are crucial in maintaining homeostatic Th17 phenotype and limiting pathogenicity during autoimmune central nervous system (CNS) inflammation. Lastly, TGFβ1 rescues impaired GC sensing in Th17Inf, suggesting therapeutic potential for treatment of steroid-resistance. Our study advances the understanding of the pathways underlying Th17 cell state regulation in vivo and highlights the clinical implications of cell-intrinsic GC biosynthesis and sensing in shaping the pathogenic potential of Th17 cells. Funding Sources This work was supported by grants from the National Institutes of Health (R01 AI176341 to A.C.A.), and the National Multiple Sclerosis Society (RG-2207-39815 to A.C.A.). D.Y. is supported by National Multiple Sclerosis Society Postdoc Fellowship (FG-2207-40160). Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)
DOI: 10.1093/jimmun/vkaf283.1194
Language: English
Subfield: Immunology
Open Access status: bronze
OpenAlex ID: W4416446291
FWCI:
Cites:
Cited by:
Related to: