PD-1 engagement and circulating Th17 effector activity during secukinumab treatment in plaque psoriasis.

Abstract

Plaque psoriasis (PP) is a chronic immune-mediated inflammatory disease driven by dysregulation of the IL-23/Th17/IL-17 axis. Although IL-17A-targeted biologics achieve robust clinical efficacy, the systemic immune remodeling accompanying successful treatment remains incompletely understood. We performed longitudinal immune profiling in seven patients with PP before treatment and after achieving a 90% reduction in the Psoriasis Area and Severity Index (PASI 90) following secukinumab therapy. Circulating T-cell subsets, programmed cell death protein 1 (PD-1)-expressing populations, cutaneous lymphocyte antigen-positive (CLA+) T cells, and plasma cytokines were analyzed by flow cytometry and multiplex assays. Ex vivo responses to the PD-1 agonist peresolimab were further evaluated in an independent cohort. At baseline, patients exhibited reduced frequencies of regulatory T cells compared with healthy controls. Following PASI 90, circulating Th17 and Th2 cell frequencies increased despite minimal sustained changes in plasma cytokine levels, suggesting dissociation between effector T-cell expansion and soluble inflammatory mediators during IL-17A blockade. Circulating CD4+CLA+ T cells were partially restored, and treatment was accompanied by increased frequencies of PD-1-expressing CD4+ T-cell subsets, which were inversely associated with disease activity over time. Ex vivo PD-1 engagement selectively suppressed IL-17A-producing CD4+ T cells while largely preserving IFN-γ production. These findings suggest that clinical improvement during IL-17A blockade is accompanied by coordinated immune remodeling rather than generalized systemic immunosuppression and that PD-1 signaling may contribute to restraining Th17 effector function during therapeutic response.