Research ArticleT CELLS

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

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Science Immunology  23 Oct 2020:
Vol. 5, Issue 52, eaba9953
DOI: 10.1126/sciimmunol.aba9953

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Poised for pathogenicity

Production of GM-CSF by T helper cells not only guides adaptive immune responses but also can contribute to the pathogenesis of autoimmune disease. Rasouli et al. used single-cell RNA sequencing, mass cytometry, and GM-CSF fate mapper mice to identify a distinct subset of T helper cells in humans and mice that specialize in sustained GM-CSF production but lack key phenotypic features of other T helper lineages. In a murine model of experimental autoimmune encephalomyelitis, these cells were poised to up-regulate IFN-γ within the central nervous system and promote development of encephalitis, processes that required the transcription factor T-bet. These results provide insight into the identity of GM-CSF–producing CD4 T cells and their function during autoimmune neuroinflammation.


Elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing T helper (TH) cells has been associated with several autoimmune diseases, suggesting a potential role in the pathogenesis of autoimmunity. However, the identity of GM-CSF–producing TH 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 THGM, that lacked expression of signature transcription factors and cytokines of established TH lineages. Using GM-CSF-reporter/fate reporter mice, we show that THGM 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 THGM cells also expressed IL-2, tumor necrosis factor (TNF), IL-3, and CCL20. THGM 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 THGM cells, it was essential for their encephalitogenicity. These findings demonstrate that THGM cells constitute a distinct population of TH cells with lineage characteristics that are poised to adopt a TH1 phenotype and promote neuroinflammation.

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