Regulatory T cells suppress GM-CSF-producing T helper cells via IL-2 modulation to restrain immunopathology

Regulatory T (T_reg) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. T_reg 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 T_reg cells' steady-state function and suppressive mechanisms that prevent autoimmune inflammation and dissect the T helper (T_H) 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 T_reg cells is crucial in restraining pathogenic GM-CSF-producing T_H cells. Our study highlights the critical role of T_reg cells and IL-2 signaling in controlling GM-CSF-producing T_H cells and type 1 responses to curb phagocyte-mediated tissue destruction.