Regulatory T cells control type 1-driven immunopathology restraining GM-CSF-producing helper T cells

SUMMARY Regulatory T (T reg ) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. T reg cell depletion or dysfunction rapidly results in fatal multiorgan inflammation linked to unrestrained effector T cell expansion, but the cytokine network underlying immunopathology, and its direct cellular mediators, remain elusive. Here, we combined gene targeting, fate-mapping tools, and high-dimensional cytometry to identify the T helper (T H ) cell-derived cytokines and responding cells that execute inflammatory tissue damage upon global loss of peripheral tolerance in mice. We found that T H cell-derived GM-CSF, but not IL-17A, directed the ensuing immunopathology and thereby mortality through recruitment of tissue-invading phagocytes and granulocytes, and enhancement of their reactive oxygen species production and phagocytic proficiency. Our study highlights the critical role of T reg cells in controlling GM-CSF- producing T H cells and type 1-responses to restrain phagocyte-mediated tissue destruction and provides a framework for the use of anti-GM-CSF therapies in patients with chronic inflammatory disorders.