Objectives <p>We aimed to explore the expression and clinical significance of TIGIT⁺CD56⁺NK cells within the peripheral blood of patients with primary Sjögren’s syndrome (pSS) in this study, as well as to examine the role of TIGIT in modulating NK cell function in individuals with pSS.</p> Methods <p>The percentage of TIGIT⁺CD56⁺NK cells was detected in the peripheral blood of 76 individuals with pSS and 63 healthy controls (HCs) using flow cytometry. The percentage of TIGIT⁺CD56⁺NK cells across various clinical features, laboratory parameters, and between active and inactive patients was analyzed. Subsequently, we analyzed the relativity between the percentage of TIGIT⁺CD56⁺NK cells and the clinical parameters in pSS patients. The percentage of TIGIT⁺CD56⁺NK cells in 10 patients with pSS was observed before and after treatment. Furthermore, we constructed receiver operating characteristic (ROC) curves to assess the diagnostic value of the percentage of TIGIT⁺CD56⁺NK cells in pSS and to predict the disease activity of pSS. We further detected the levels of cytokines secreted by TIGIT⁺ and TIGIT⁻NK cells in 5 pSS patients to assess the function of NK cells.</p> Results <p>In patients with pSS, there was a reduction in the percentage of TIGIT⁺CD56⁺NK cells, particularly among those with active disease. The percentage of TIGIT⁺CD56⁺NK cells exhibited a significant reduction in patients with pSS accompanying xerostomia, decayed tooth, glandular swelling, fatigue, arthralgia, cutaneous manifestations, renal tubular acidosis (RTA), interstitial lung disease (ILD), leukopenia, lymphopenia, increased serum globulin, increased ESR, increased IgG, increased IgA, and positive tests for anti-Ro52, anti-Ro60, and rheumatoid factor (RF), compared to those with negative results. TIGIT expression on CD56⁺ NK cells exhibited a negative relevance with ESR, serum globulin levels, RF, IgG levels, ESSDAI scores, and ESSPRI scores. After treatment, the TIGIT⁺CD56⁺NK cells percentage increased notably. The ROC curve demonstrated that the level of TIGIT⁺CD56⁺NK cell percentage exhibited an excellent capacity for differentiating pSS and predicting disease activity. The expression levels of CD69, Ki67, perforin, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were found to be lower in TIGIT⁺CD56⁺NK cells compared to TIGIT⁻CD56⁺NK cells among patients with pSS. Furthermore, we discovered that expression levels of perforin and TNF-α were negatively related with that of TIGIT⁺CD56⁺NK cells.</p> Conclusion <p>Our research indicated that a reduction in TIGIT⁺CD56⁺NK cell percentage was related with clinical characteristics, laboratory indicators, disease progression, and outcome prediction in patients with pSS. TIGIT negatively regulates the function of NK cells, and reduced TIGIT⁺CD56⁺NK cells contribute to the development of pSS disease. In brief, TIGIT⁺CD56⁺NK cells might function as a prospective indicator for the assessment of disease progression and outcome prediction in pSS, and may even be regarded as a potential candidate target for immunotherapy in pSS.</p> <p><Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec colname="c1" colnum="1" /> <colspec colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p>Key Points</p> <p>• <i>In patients with pSS, there was a reduction in the percentage of TIGIT+CD56+NK cells, particularly among those with active disease.</i></p> <p>• <i>Our research indicated that a reduction in TIGIT+CD56+NK cell percentage was related with clinical characteristics, laboratory indicators, disease progression, and outcome prediction in patients with pSS.</i></p> <p>• <i>TIGIT negatively regulates the function of NK cells, and reduced TIGIT+CD56+NK cells contribute to the development of pSS disease.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>