A distinct GM-CSF+ T helper cell subset requires T-bet to adopt a TH1 phenotype and promote neuroinflammation

Elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing T helper (T-H) 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-H 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 CD45RA(-)CD4(+) T cells in blood of healthy individuals including a population of GM-CSF-producing cells, known as T(H)GM, that lacked expression of signature transcription factors and cytokines of established T-H lineages. Using GM-CSF-reporter/fate reporter mice, we show that T(H)GM 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 T(H)GM cells also expressed IL-2, tumor necrosis factor (TNF), IL-3, and CCL20. T(H)GM cells maintained their phenotype through several cycles of activation but up-regulated expression of T-bet and interferon-gamma (IFN-gamma) 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 T(H)GM cells, it was essential for their encephalitogenicity. These findings demonstrate that T(H)GM cells constitute a distinct population of T-H cells with lineage characteristics that are poised to adopt a T(H)1 phenotype and promote neuroinflammation.