A distinct GM-CSF T helper cell subset requires T-bet to adopt a T1 phenotype and promote neuroinflammation.

Elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing T helper (T) cells has been associated with several autoimmune diseases, suggesting a potential role in the pathogenesis of autoimmunity. However, the identity of GM-CSF–producing T cells has not been closely examined. Using single-cell RNA sequencing and high-dimensional single-cell mass cytometry, we identified eight populations of antigen-experienced CD45RACD4 T cells in blood of healthy individuals including a population of GM-CSF–producing cells, known as TGM, that lacked expression of signature transcription factors and cytokines of established T lineages. Using GM-CSF-reporter/fate reporter mice, we show that TGM cells are present in the periphery and central nervous system in a mouse model of experimental autoimmune encephalomyelitis. In addition to GM-CSF, human and mouse TGM cells also expressed IL-2, tumor necrosis factor (TNF), IL-3, and CCL20. TGM cells maintained their phenotype through several cycles of activation but up-regulated expression of T-bet and interferon-γ (IFN-γ) upon exposure to IL-12 in vitro and in the central nervous system of mice with autoimmune neuroinflammation. Although T-bet was not required for the development of TGM cells, it was essential for their encephalitogenicity. These findings demonstrate that TGM cells constitute a distinct population of T cells with lineage characteristics that are poised to adopt a T1 phenotype and promote neuroinflammation.