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

• Published in: Immunity (Cambridge, Mass.) Vol. 50; no. 5; pp. 1289 - 1304.e6
• Main Authors: Komuczki, Juliana, Tuzlak, Selma, Friebel, Ekaterina, Hartwig, Tom, Spath, Sabine, Rosenstiel, Philip, Waisman, Ari, Opitz, Lennart, Oukka, Mohammed, Schreiner, Bettina, Pelczar, Pawel, Becher, Burkhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.05.2019; Elsevier Limited
• Subjects: Ablation; Bioaccumulation; Cell fate; Cerebrospinal fluid; Coding; Colony-stimulating factor; CRISPR; CXCR6; Cytokines; EAE; epigenetic modification; Epigenetics; Fate maps; fate-map; Genetic engineering; GM-CSF; Granulocyte-macrophage colony stimulating factor; Helper cells; IL-1R; IL-1β; IL-23R; Immunological memory; In vivo methods and tests; Inflammation; Inflammatory diseases; Interleukin 1 receptors; Interleukin 23; Interleukin 6; Lymphocytes; Lymphocytes T; Mapping; Medical research; Multiple sclerosis; pathogenic T cells; Pathogenicity; Pathogens; Phagocytes; Progeny; Psoriasis; reporter; Tissues; fate-map; IL-23R; GM-CSF; multiple sclerosis; EAE; epigenetic modification; reporter; cytokines; CXCR6; IL-1R; pathogenic T cells
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2019.04.006

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. [Display omitted] •FROG mice permit reporting and fate-mapping of GM-CSF-expressing cells•GM-CSF production by Th cells is vital for phagocyte invasion and tissue inflammation•The cytokines IL-23 and IL-1β are indispensable for GM-CSF expression•IFN-γ and IL-17A cannot maintain pathogenicity in the absence of GM-CSF in Th cells GM-CSF is a critical cytokine in the development of tissue inflammation. Komuzcki et al. use a fate-mapping and reporter system to demonstrate that GM-CSF production by CNS-infiltrating T helper cells is crucial for phagocyte invasion and neuroinflammation. Pathogenicity was lost in the absence of GM-CSF expression despite the presence of IFN-γ- and IL-17-producing T helper cells in the CNS.