Fate-Mapping of GM-CSF Expression Identifies a Discrete Subset of Inflammation-Driving T Helper Cells Regulated by Cytokines IL-23 and IL-1β

Immunity. 2019 May 21;50(5):1289-1304.e6. doi: 10.1016/j.immuni.2019.04.006. Epub 2019 May 9.


Pathogenic lymphocytes initiate the development of chronic inflammatory diseases. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) (encoded by Csf2) is a key communicator between pathogenic lymphocytes and tissue-invading inflammatory phagocytes. However, the molecular properties of GM-CSF-producing cells and the mode of Csf2 regulation in vivo remain unclear. To systematically study and manipulate GM-CSF+ cells and their progeny in vivo, we generated a fate-map and reporter of GM-CSF expression mouse strain (FROG). We mapped the phenotypic and functional profile of auto-aggressive T helper (Th) cells during neuroinflammation and identified the signature and pathogenic memory of a discrete encephalitogenic Th subset. These cells required interleukin-23 receptor (IL-23R) and IL-1R but not IL-6R signaling for their maintenance and pathogenicity. Specific ablation of this subset interrupted the inflammatory cascade, despite the unperturbed tissue accumulation of other Th subsets (e.g., Th1 and Th17), highlighting that GM-CSF expression not only marks pathogenic Th cells, but that this subset mediates immunopathology and tissue destruction.

Keywords: CXCR6; EAE; GM-CSF; IL-1R; IL-23R; cytokines; epigenetic modification; fate-map; multiple sclerosis; pathogenic T cells; reporter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Inflammation / genetics
  • Inflammation / pathology
  • Interferon-gamma / metabolism
  • Interleukin-1beta / immunology*
  • Interleukin-23 Subunit p19 / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, CXCR6 / metabolism
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology
  • Receptors, Interleukin-1 Type I / genetics
  • Receptors, Interleukin-1 Type I / immunology
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*
  • Tumor Necrosis Factor-alpha / metabolism


  • Cxcr6 protein, mouse
  • IFNG protein, mouse
  • IL1B protein, mouse
  • IL1R1 protein, mouse
  • Il23a protein, mouse
  • Interleukin-1beta
  • Interleukin-23 Subunit p19
  • Receptors, CXCR6
  • Receptors, Interleukin
  • Receptors, Interleukin-1 Type I
  • Tnf protein, mouse
  • Tumor Necrosis Factor-alpha
  • interleukin-23 receptor, mouse
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor