Single cell sequencing identifies clonally expanded synovial CD4⁺ T_PH cells expressing GPR56 in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease affecting synovial joints where different CD4⁺ T cell subsets may contribute to pathology. Here, we perform single cell sequencing on synovial CD4⁺ T cells from anti-citrullinated protein antibodies (ACPA)+ and ACPA- RA patients and identify two peripheral helper T cell (T_PH) states and a cytotoxic CD4⁺ T cell subset. We show that the adhesion G-protein coupled receptor 56 (GPR56) delineates synovial CXCL13^high T_PH CD4⁺ T cells expressing LAG-3 and the tissue-resident memory receptors CXCR6 and CD69. In ACPA- SF, T_PH cells display lower levels of GPR56 and LAG-3. Further, most expanded T cell clones in the joint are within CXCL13^high T_PH CD4⁺ T cells. Finally, RNA-velocity analyses suggest a common differentiation pathway between the two T_PH clusters and effector CD4⁺ T cells. Our study provides comprehensive immunoprofiling of the synovial CD4⁺ T cell subsets in ACPA+ and ACPA- RA.