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.