Abstract: Objective To investigate the effect of co-stimulatory molecule B7-H4 on the regulation of T cell subsets in (NOD) mice induced by SjÖgren's syndrome (SS). Methods Female NOD mice were randomly divided into baseline group, normal saline (NS) group, B7-H4-Fc protein group, IgG2a-Fc group. After 0 days and 30 days, The mice were sacrificed after being anesthetized, and the spleen and submandibular glands were taken out. The changes of lymphocyte subsets in spleen single cell suspension were detected by flow cytometry, and the submandibular gland tissue was stained with HE and immunohistochemistry. Results Costimulatory molecule B7-H4 protein was mainly expressed in cytoplasm of submandibular gland ductal endothelial cells in NOD mice. A low expression of B7-H4 protein was found in a large number of lymphocytes infiltrated in the submandibular gland. The degree of inflammatory infiltration of submandibular gland in NOD mice was significantly reduced after intraperitoneal injection of B7-H4-Fc fusion protein at day 30. The percentages of CD4+Foxp3+Tcell/CD4+Tcell in spleen were significantly increased in B7-H4-Fc group compared with IgG2a-Fc group, NS group and baseline group respectively (all P<0.05). The percentage of CD4+IFN-γ+Tcell/CD4+Tcell in B7-H4-Fc group was significantly lower than that in IgG2a-Fc group, NS group and baseline group (all P<0.05). There was no significant difference in the proportion of CD4+IL-17+T cells in the spleen between the three groups in the proportion of CD4+T cells. Conclusions B7-H4 protein can delay the infiltration of lymphocyte in the submandibular gland of NOD mice, reduce the level of inflammatory cytokines and inhibit the progress of autoimmune inflammation.