GPR56 Outperforms CD319 as a Discriminative Marker for CD4 + Cytotoxic T Lymphocytes and Is Elevated in Primary Sjögren's Syndrome

ABSTRACT Cytotoxic T lymphocytes (CTLs), especially CD4 + CTLs, play a critical role in immune responses against infections and cancers. Nevertheless, the surface markers that define CD4 + CTLs remain incompletely characterised, which limits their diagnostic and therapeutic potential. In this study, we investigate CD319 (SLAMF7) and GPR56 as potential surface markers of CD4 + CTLs, with a focus on their cytotoxic functions and relevance in primary Sjögren's syndrome (pSS). Using single‐cell RNA sequencing and flow cytometry, we detected strong co‐expression of GPR56 with cytotoxic effector molecules such as granzyme B in CD4 + T cells. Notably, pSS patients showed an elevated frequency of CD4 + GPR56 + T cells, which was associated with disease severity, indicating their potential contribution to pSS pathogenesis. Comparative transcriptomic analysis revealed distinct gene expression profiles between CD4 + GPR56 + and CD4 + GPR56 − T cells, with enriched pathways related to immune activation and cytotoxicity. Together, our results identify GPR56 as a novel and functionally significant surface marker for CD4 + CTLs, providing new insights into their role in autoimmune disorders and their potential for targeted therapeutic strategies.