The role and function of CTLA-4 in Sjögren's syndrome

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a key immune checkpoint involved in immune regulation. CTLA-4 inhibitors have been widely used in cancer therapy and have attracted increasing attention in autoimmune diseases such as Sjögren's syndrome (SS) in recent years. CTLA-4 modulates multiple immune processes, including genetic susceptibility, immune cell subsets, and inflammatory cytokine levels. CTLA-4, together with co-inhibitory receptors including Programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), forms a multi-layered immunosuppressive network. It modulates the balance of T cell subsets, regulates B cell receptor (BCR)-related pathways and downstream molecules such as Bruton's tyrosine kinase (BTK), and thereby orchestrates cellular and humoral immunity. CTLA-4 inhibitors used in cancer immunotherapy may trigger immune-related adverse events resembling Sjögren's syndrome. Abatacept, a CTLA-4-Ig fusion protein that blocks T-cell costimulation, has been investigated as a therapeutic candidate for primary Sjögren's syndrome (pSS). Open-label clinical studies consistently indicate that abatacept reduces disease activity, improves salivary gland function, and alleviates systemic symptoms. However, findings from randomized controlled trials remain inconsistent: some show no significant clinical benefit compared with placebo, whereas others demonstrate improvements in clinical indices, patient-reported outcomes, and laboratory parameters. Currently, the precise mechanism of CTLA-4 in the pathogenesis of Sjögren's syndrome\ remains incompletely clarified, and high-quality evidence supporting CTLA-4-targeted therapy is still limited. Further research is needed to validate the therapeutic value and optimal application of abatacept and other CTLA-4-modulating agents in Sjögren's syndrome.