Regulatory T (Treg) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. Treg cell depletion or dysfunction results in fatal multiorgan inflammation linked to unrestrained effector T cell expansion. Here, we combine in vivo gene targeting and fate-mapping with high-dimensional cytometry to identify Treg cells' steady-state function and suppressive mechanisms that prevent autoimmune inflammation and dissect the T helper (TH) cell-derived cytokines and responding cells executing tissue damage upon global loss of peripheral tolerance. We unveil that type 1 cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)γ, but not interleukin (IL)-17A, direct the ensuing immunopathology and mortality. GM-CSF orchestrates tissue invasion by monocytes and granulocytes and enhances their reactive oxygen species production and phagocytic capability. IL-2 modulation by Treg cells is crucial in restraining pathogenic GM-CSF-producing TH cells. Our study highlights the critical role of Treg cells and IL-2 signaling in controlling GM-CSF-producing TH cells and type 1 responses to curb phagocyte-mediated tissue destruction.
Keywords: CP: Immunology; Foxp3; GM-CSF; IL-2; T(reg) suppressor function; inflammation; regulatory T cells; tissue-invading phagocytes; type 1 responses.
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