摘要
Graves*orbitopathy(GO),the most severe manifestation of Graves'hyperthyroidism(GH),is an autoimmune-mediated inflammatory disorder,and treatments often exhibit a low efficacy.CD4+T cells have been reported to play vital roles in GO progression.To explore the pathogenic CD4-f T cell types that drive GO progression,we applied single-cell RNA sequencing(scRNA-Seq),T cell receptor sequencing(TCR-Seq),flow cytometry,immunofluorescence and mixed lymphocyte reaction(MLR)assays to evaluate CD4+T cells from GO and GH patients.scRNA-Seq revealed the novel GO-spedfic cell type CD4+cytotoxic T lymphocytes(CTLs),which are characterized by chemotactic and inflammatory features.The clonal expansion of this CD4+CTL population,as demonstrated by TCR-Seq,along with their strong cytotoxic response to autoantigens,localization in orbital sites,and potential relationship with disease relapse provide strong evidence for the pathogenic roles of GZMB and IFN-y-secreting CD4+CTLs in GO.Therefore,cytotoxic pathways may become potential therapeutic targets for GO.
基金
supported by the National Key R&D Program of China(Grant nos.2018YFC1311500(B.S.),2017YFC0907500(K.Y.)and 2018YFC0910400(K.Y.))
National Science Foundation of China(NSFC)(Grant nos.81970679(B.S.),81500690(Y.W.),and 31671372(K.Y.))
Natural Science Foundation of Shaanxi Province(2018JM70990(Y.W.))
Key Research and Development Project of Shaanxi Province(Grant no.2017ZDXM-SF-060(B.S.))
Fundamental Research Funds for the Central Universities(1191329875(Y.W.))
the China Postdoctoral Science Foundation(224646(Y.W.)).
