Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity

• Published in: Cell 2021-12, Vol.184 (26), p.6281-6298.e23
• Main Authors: Schnell, Alexandra, Huang, Linglin, Singer, Meromit, Singaraju, Anvita, Barilla, Rocky M., Regan, Brianna M.L., Bollhagen, Alina, Thakore, Pratiksha I., Dionne, Danielle, Delorey, Toni M., Pawlak, Mathias, Meyer zu Horste, Gerd, Rozenblatt-Rosen, Orit, Irizarry, Rafael A., Regev, Aviv, Kuchroo, Vijay K.
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity; Cell Movement; Clone Cells; CNS inflammation; Encephalomyelitis, Autoimmune, Experimental - immunology; fate-mapping; GM-CSF; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; gut-brain axis; Homeostasis; Humans; IFNγ; IL-17; Interferon-gamma - metabolism; Interleukin-17 - metabolism; Intestines - immunology; Mice; Mice, Inbred C57BL; multiple sclerosis; Organ Specificity; Receptors, Antigen, T-Cell - metabolism; Receptors, CXCR6 - metabolism; Receptors, Interleukin - metabolism; Reproducibility of Results; RNA - metabolism; RNA-Seq; Signaling Lymphocytic Activation Molecule Family - metabolism; Single-Cell Analysis; Spleen - metabolism; Stem Cells - metabolism; stem-like T cells; Th17 cells; Th17 Cells - immunology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.11.018

While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFN-γ+ CXCR6+ T cells. Our study defines a direct in vivo relationship between IL-17+ non-pathogenic and GM-CSF+ and IFN-γ+ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease. [Display omitted] •Combined scRNA/TCR-seq reveals extensive heterogeneity of tissue Th17 cells•Th17 cells exhibit strong tissue-specific signatures•Stem-like SLAMF6+ and pathogenic CXCR6+ Th17 populations are induced in autoimmunity•IL-23 converts the stem-like IL-17+ to the pathogenic GM-CSF+ IFN-γ+ population Stem-like Th17 cells that exert homeostatic effects in the intestine form a reservoir from which pathogenic Th17 cells can differentiate and contribute to neuroinflammatory pathology in experimental autoimmune encephalomyelitis.