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

Cell Rep. 2025 May 27;44(5):115642. doi: 10.1016/j.celrep.2025.115642. Epub 2025 May 1.

Abstract

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.

MeSH terms

  • Animals
  • Granulocyte-Macrophage Colony-Stimulating Factor* / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor* / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-2* / immunology
  • Interleukin-2* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Reactive Oxygen Species / metabolism
  • T-Lymphocytes, Helper-Inducer* / immunology
  • T-Lymphocytes, Helper-Inducer* / metabolism
  • T-Lymphocytes, Regulatory* / immunology
  • T-Lymphocytes, Regulatory* / metabolism

Substances

  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Interleukin-2
  • Interferon-gamma
  • Reactive Oxygen Species