TCR activation couples inflammatory Th17 responses to regulatory gene programs in human IL1R1⁺ Th17 cells.

ABSTRACT: Human Th17 cells mediate epithelial barrier–protective immunity, but sustained Th17 inflammation can cause tissue injury. IL1R1 identifies a human memory Th17 subset with enhanced inflammatory potential and regulatory-associated transcriptional features, yet how IL1R1⁺ and IL1R1⁻ Th17 cells respond to TCR activation versus IL-1β stimulation remains poorly defined. We sorted IL1R1⁺ and IL1R1⁻ human memory Th17 cells and performed single-cell RNA sequencing after culture in media, IL-1β, or anti-CD3/CD28/CD2 stimulation. TCR activation induced extensive transcriptional remodeling in both populations, but the resulting programs diverged by IL1R1 status. CD3-activated IL1R1⁻ Th17 cells preferentially expressed interferon-associated effector programs, whereas CD3-activated IL1R1⁺ Th17 cells diversified into effector Th17 and regulatory-associated states, including states enriched for canonical Th17 genes such as IL17A, IL17F, IL22, IL26, and CCL20, and others expressing regulatory-associated genes including FOXP3, IL2RA, CTLA4, TIGIT, IL1R2, LAG3, and LRRC32. RNA velocity and velocity-derived pseudo-time analyses identified a putative transcriptional trajectory from activated effector Th17 cells through regulatory-associated Th17 states toward effector Treg-like states. Regulatory-associated transcripts were detectable at baseline and persisted despite Th17-polarizing cytokines. By contrast, IL-1β alone induced a restricted inflammatory program. In acne lesional skin, effector Th17 and effector Treg populations formed a local transcriptional axis that partially recapitulated the in vitro program. These findings identify IL1R1⁺ Th17 cells as a regulatory-competent inflammatory subset in which TCR activation may couple Th17 immunity to mechanisms that restrain tissue-damaging inflammation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE338037 | GEO | 2026/07/15

REPOSITORIES: GEO