A novel CD4+CTL subtype characterized by chemotaxis and inflammation is involved in the pathogenesis of Graves' orbitopathy

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+ 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-specific 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-gamma-secreting CD4+ CTLs in GO. Therefore, cytotoxic pathways may become potential therapeutic targets for GO.

Automated summary

Research has revealed a novel cell type called CD4+ cytotoxic T lymphocytes (CTLs) that play crucial roles in driving Graves' orbitopathy (GO). These CTLs exhibit chemotactic and inflammatory features, show strong cytotoxic response to autoantigens, localize in orbital sites, and potentially relate to disease relapse, providing new insights into the pathogenesis of GO.