IFNα Promotes The Differentiation Of Th1-like Treg Cells In The Development Of SLE

Objective:Systemic lupus erythematosus(SLE)is an autoimmune disease involving multiple organs,characterized by highly activated proliferation of T-B cells,autoimmune dysfunction,and production of mutiple autoantibodies.Besides traditional immunosuppressants,a variety of targeted drugs have been put into use for the treatment of SLE.However,there is still a lack of effective individualized treatment for SLE.T regulatory cells(Tregs)are a class of CD4~+T cells with immunosuppressive ability,which can inhibit excessive immune activation of T cells to avoid damage to the body.Abnormal function of Tregs may lead to the occurrence of autoimmune disease.Under pathological conditions,the plasticity of Treg cells is enhanced,and some Treg cells can obtain the type 1 helper T(Th1)cell phenotype with acquiring pro-inflammatory ability through external stimulation,which is called Th1-like Treg cells,while the inhibitory ability of Treg cells is decreased.It is thought to be an incapacitated state of Treg cells.Interferon-I(IFN),especially IFN-α,has been proved to be able to promote Th1-like phenotype and play an important role in the development of SLE.However,whether IFNαcan promote the differentiation of Th1-like Treg cells remain unclear.Therefore,the purpose of this study is to explore whether IFNαcan induce the abnormal increase of Th1-like Treg cells to participate in the pathogenesis of SLE providing new ideas and new targets for the treatment of SLE.Method:SLE patients and Health donor(HD)were selected as subjects.Peripheral blood was extracted to obtain Peripheral blood mononuclear cells by using lymphocyte separation solution cells(PBMCs),the expression of Th1 cells,Treg cells related markers were detected by flow cytometry,and the proportion of Th1 cells,Th1-like Treg cells and the activation state of T cells were analyzed.General data and clinical test results of the subjects were collected to analyze the correlation between Th1-like Treg cells and disease severity.Serum cytokine concentrations in patients and healthy subjects were measured with Luminex kit.PBMCs and CD4~+T cells sorted by immunomagnetic beads from subjected were cultured in vitro,the activation time of T cell receptor(TCR)was detected.Given IFNα,the differentiation of Th1-like Treg cells and plasma cells and the activation of JAK/STAT pathway were detected by flow cytometry,and the direct effect of IFNαon T cell differentiation was analyzed.Finally,exogenous TIGIT agonist was given to improve the differentiation of Th1-like Treg cells mediated by IFNα.Result:Compared to healthy control group,the number of Th1 cells and Th1-like Treg cells were signicantly increased in peripheral blood of SLE patients,and increased degree of T cell activation was observed.Th1-like Treg cells in peripheral blood of SLE patients were positively correlated with serum CRP level.The serum levels of cytokines IFNα,IFNβ,IFNγ,IL-2,IL-6,IL-12 and IL-21 were highly increased in SLE patients.IFNαpromotes Th1-like Treg,plasma cell differentiation and STAT4 phospgorylation.After exogenous intervention with TIGIT agonist,the proportion of Th1-like Treg cells and plasma cells decreased,and the phosphorylation levels of STAT4 decreased.Conclusion:Abnormal expansion of Th1-like Treg cells in peripheral blood of SLE patients,and high activation of T cells were observed in SLE patients,the percentage of Th1-like Treg cells are correlated with disease severity.Serum cytokine levels are elevated in SLE patients.IFN-αpromoted the differentiation of Treg cells into Th1-like Treg cells and plasmacytoid lymphocyte by activating STAT4.Exogenous TIGIT agonists inhibit IFNα-mediated Treg differentiation into Th1-like Treg cells,enhancing the inhibitory function of Treg cells,and providing a new direction for the treatment of SLE.