JAK1/2 Inhibition Restores Tissue Integrity by Rewiring Type 1/2 Immunity Toward Targetable IL-17 Responses

Abstract

Effective immune responses require coordinated communication between immune and epithelial cells to eliminate pathogens while limiting tissue damage. Disruption of this balance drives chronic inflammation and progressive tissue destruction. The Janus kinase (JAK) pathway coordinates cytokine signaling across these compartments and has emerged as a therapeutic target in inflammatory diseases. However, the consequences of JAK inhibition within a complex inflammatory environment remain incompletely understood. Here, we dissect the molecular, cellular, immunological and phenotypical effects of topical JAK1/2 inhibition in a chronic model of tissue-destructive skin inflammation driven by barrier dysfunction and bacterial superinfection. Single-cell transcriptomics and functional profiling revealed that JAK1/2 blockade selectively suppressed pathogenic CD8 T cells and their IFN-{gamma} production while shifting Th2-polarized CD4 T cells toward a Th17 phenotype, preserving type 3 immunity consisting of IL-17A-producing {gamma}{delta}-T cells and neutrophil responses. This immune rebalancing occurs rapidly and concomitantly with the restoration of epithelial barrier integrity through tight junction reinforcement, followed by recovery of antimicrobial defenses and reduced bacterial burden. Combination of JAK1/2 and IL-17A blockade further improved tissue homeostasis by targeting residual type 3-driven pathology. Thus, JAK1/2 inhibition acts as selective immunomodulator rather than a broad immunosuppressant, targeting pathogenic type 1/2 responses while preserving type-3-associated antimicrobial defense programs. These findings reveal how JAK1/2 inhibition coordinates immune rebalancing with epithelial repair and support its therapeutic potential in chronic type 1/2-driven inflammatory disease, while identifying residual IL-17A-mediated pathology as a target for combination therapy.