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

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.