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

Cell Mol Immunol. 2021 Mar;18(3):735-745. doi: 10.1038/s41423-020-00615-2. Epub 2021 Jan 29.

Abstract

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

Keywords: CD4+ cytotoxic T lymphocytes; Graves’ orbitopathy; single-cell RNA sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology*
  • Chemotaxis*
  • Graves Ophthalmopathy / etiology
  • Graves Ophthalmopathy / metabolism
  • Graves Ophthalmopathy / pathology*
  • Humans
  • Inflammation / complications*
  • RNA-Seq
  • Receptors, Antigen, T-Cell / metabolism*
  • Single-Cell Analysis / methods*
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • Receptors, Antigen, T-Cell