Structural Superimposition

Abstact

Sjogren's disease (SjD) is a T cell-driven autoimmune condition strongly associated with the HLA-DRB1 *03:01 allele and autoantibodies against the Ro60 protein. Previous studies have identified deficiencies in regulatory T cells (Treg) in patients, indicating a breakdown in immune tolerance. Current treatments remain limited to symptomatic relief or broad immunosuppression, without addressing the underlying immune dysregulation. In this study, we present the first preclinical evidence supporting a TCR-engineered Treg (TCR-Treg) therapy specifically targeting SjD. We designed a TCR-Treg that recognizes a dominant epitope of the Ro60 antigen (Ro60(369-383)) presented by HLA-DRB1 *03:01 and demonstrate that these cells can selectively suppress autoreactive T cells more effectively than polyclonal Treg. These findings underscore the pathogenic significance of the Ro-HLA-DRB1 *03:01 axis and provide proof-of-concept for a targeted, antigen-specific Treg therapy. This approach offers a promising strategy to restore immune tolerance and represents a potential disease-modifying treatment for genetically defined subsets of patients with SjD.