Identification of a shared antigen linking CD4⁺ T and B cell pathology in Sjögren's disease.

Abstract

Sjögren's disease (SjD) is an autoimmune disorder characterized by lymphocytic infiltration of exocrine glands. Although B cells producing anti-Ro60 autoantibodies are frequently found in salivary gland lesions, the antigen specificity of CD4⁺ T cells has remained unclear. Given accumulating evidence for T cell involvement in local autoantibody production, we comprehensively investigated Ro60 reactivity among lesion-infiltrating CD4⁺ T cells. Over 200 T cell receptors (TCRs) enriched in salivary glands from Japanese and Caucasian patients with SjD were screened using a TCR reporter system, identifying 13 Ro60-reactive TCRs predominantly expressed in T peripheral helper/T follicular helper subset, along with human leukocyte antigen alleles linked to SjD susceptibility. Ro60 was efficiently phagocytosed by antigen-presenting cells in the presence of autoantibodies and presented to Ro60-specific T cells, triggering their activation. This suggests that Ro60-specific B and CD4⁺ T cells orchestrate a pathological loop in salivary glands. Our study provides the first molecular identification of a major CD4⁺ T cell antigen in systemic autoimmunity and highlights coordinated T-B cell responses against a shared autoantigen.