Altered CD226/TIGIT expressions were associated with activated NK phenotypes in primary anti-phospholipid syndrome and affected by IL-4/JAK pathway.

Natural killer (NK) cells were reported to be involved in the pathogenesis of primary antiphospholipid syndrome (pAPS). Immunosuppressive receptor TIGIT and activating receptor CD226 are specifically expressed on NK cells with competitive functions. This study aims to investigate the expression diversities of CD226/TIGIT on NK subsets and their associations with NK subsets activation phenotypes and potential clinical significance, furthermore, to explore potential cause for CD226/TIGIT expression diversities in pAPS. We comparatively assessed the changes of CD56brightNK, CD56dimNK and NK-like cells in seventy pAPS patients compared with control groups, including SLE, asymptomatic-carriers of aPLs, and healthy controls (HCs) and their expression diversities of CD226/TIGIT by flow cytometry. CD25, CD69, CD107α expression and IFN-γ secretion levels of NK subsets were detected to determine the potential association of CD226/TIGIT expression with NK subsets activation. CD226/TIGIT expression levels were compared among different subgroups divided by aPLs status. Moreover, in-vitro cultures were conducted to explore the potential mechanisms of CD226/TIGIT expression imbalance. Results: CD56brightNK and CD3+CD56+NK-like cells were significantly increased while CD56dimNK cells were obviously decreased in pAPS, and CD56brightNK and NK-like cells exhibited significantly higher CD226 but lower TIGIT expressions. CD226+CD56brightNK and TIGIT-CD56brightNK cells show higher CD69 expression and IFN-γ secretion capacity, and CD226+NK-like and TIGIT-NK-like cells showed higher expressions of CD25 and CD69 but lower apoptosis than CD226- and TIGIT+CD56brightNK/NK-like cells, respectively. The imbalanced CD226/TIGIT expressions were most significant in aPLs triple-positive group. Expression imbalanced of CD226/TIGIT on CD56brightNK and NK-like cells were aggravated after IL-4 stimulation and recovered after tofacitinib blocking. Conclusion: Our data revealed significant imbalanced CD226/TIGIT expressions on NK cells in pAPS, which closely associated with activated NK subsets phenotypes and more complicated autoantibody status. CD226/TIGIT imbalanced may be affected by IL-4/JAK pathway activation.