Single-Cell RNA Sequencing of Thyroid Tissues Reveals Pathogenesis of Graves' Disease.

Abstract

Graves' disease (GD) is an autoimmune disorder primarily targeting the thyroid tissue. While major histocompatibility complex (MHC)-dependent B cell activation and thyroid-stimulating hormone receptor (TSHR) autoantibody production are central to GD, the intrathyroidal immune landscape remains largely unexplored. Through single-cell RNA sequencing (scRNA-seq), this work constructed a comprehensive immune cell atlas, revealing dominant IFN-γ-secreting CD4⁺ T cells, expanded T peripheral helper (Tph) cells, CD11c⁺ atypical B cells, and CD8⁺ effector T cells. Notably, stress-surveilling γδ T/NK cells are enriched in GD. Thyroid follicular cells (TFCs) in GD exhibited a stressed phenotype, and in vitro functional assays showed that they promote γδ T cell activation and proliferation. γδ T cells may recruit conventional type 1 dendritic cells (cDC1) via XCL1/XCL2, suggesting a potential link to adaptive immune reorganization. These findings suggest an additional MHC-independent pathway linking TFC stress to autoimmune activation via γδ T cells in GD pathogenesis.