Alteration of CD226/TIGIT immune checkpoint on T cells in the pathogenesis of primary Sjögren's syndrome

Objectives: Hyperactivity of T lymphocytes might play an important role in the pathogenesis of primary Sjögren's syndrome (pSS). CD226/T cell immunoglobulin and ITIM domain (TIGIT) pathway is a newly identified immune checkpoint involved in the pathogenesis of cancer and rheumatic diseases. However, its role in the pathophysiology of pSS is obscure. Hence, this study aimed to explore the potential role of CD226/TIGIT expression on T cells in the pathogenesis of pSS. Methods: In patients with pSS, other rheumatic disease controls (DCs), and healthy controls (HCs), the expression of CD226 and TIGIT on T cells along with their activity following stimulation were detected by flow cytometry. The correlations between the expression of CD226 and TIGIT on T cells and clinical data were analyzed. Results: The frequencies of CD226/TIGIT expressing CD4⁺ and CD8⁺ T cells were significantly higher in patients with pSS than in HCs and DCs. Among them, the TIGIT/CD226 expressing CD4⁺ T cells closely correlated with pSS disease activity: the percentages of CD4⁺CD226⁺ and CD4⁺TIGIT⁺ T cells were significantly higher in the active pSS than the inactive pSS. The proportion of CD4⁺TIGIT⁺ T cells positively correlated with the erythrocyte sedimentation rate. Further in vitro analysis revealed that CD4⁺CD226⁺ T cells exerted superior effector function than the CD226^- counterparts in both pSS and HCs. TIGIT was preferably expressed on activated cells, and the activity of CD4⁺TIGIT⁺ T cells was comparable with CD4⁺TIGIT⁻ T cells in HCs. However, in pSS, CD4⁺TIGIT⁺ T cells showed enhanced activity than the CD4⁺ TIGIT⁻ T cells. Conclusion: CD226/TIGIT checkpoint molecules were over-expressed on T cells in pSS. Proportional and functional alteration of CD226/TIGIT expressing CD4⁺ T cells may be involved in the pathogenesis of pSS, and be a potential novel therapeutic target for the disease.