Effect of CXCR5, PD-1 and ICOS on B-cell responses and relevance to myasthenia gravis

Abstract

Objectives: T follicular helper (Tfh) cells regulate B-cell responses within germinal centres primarily via programmed cell death protein 1 (PD-1) and inducible T-cell costimulator (ICOS), whereas CXC chemokine receptor type 5 (CXCR5)-negative T peripheral helper (Tph) cells provide similar support extra-follicularly. Both subsets contribute to the pathogenesis of acetylcholine receptor-antibody-positive myasthenia gravis (AChR-MG). This study investigated the roles of PD-1, ICOS and CXCR5 in T-cell-mediated B-cell activation to identify therapeutic targets for MG.

Methods: CD4 T cells from 10 healthy controls and six untreated AChR-MG patients were sorted by CXCR5, PD-1 and ICOS expression, stimulated with anti-CD3/CD28, and co-cultured with autologous CD19 B cells. Plasmablast differentiation, total AChR-IgG and cytokine productions were measured.

Results: In healthy donors, PD-1+ or ICOS+ Tph cells modestly enhanced plasmablasts and IgG production, while CXCR5+ Tfh cells co-expressing PD-1 or ICOS induced significantly stronger B-cell responses. In AChR-MG patients, PD-1 expressing T cells promoted plasmablasts, antibody production and cytokine secretion regardless of CXCR5, with amplified effects in CXCR5+ co-cultures.

Conclusions: PD-1 expression on CD4+ T cells is associated with increased B-cell helper capacity. This effect is more pronounced in Tfh-related contexts and is linked to dysregulated humoral immune responses in MG. PD-1 appears to play a central role in the pathogenesis of MG, primarily through Tfh cell activity.