Single-cell clonotype tracing of tissue Th17 cells during CNS autoimmunity reveals the conversion of intestinal homeostatic cells to pathogenic cells

Autor: Alexandra Schnell, Linglin Huang, Meromit Singer, Anvita Singaraju, Alina Bollhagen, Pratiksha I Thakore, Danielle Dionne, Toni M Delorey, Mathias Pawlak, Rafael Irizarry, Aviv Regev, Vijay K Kuchroo
Rok vydání: 2021
Předmět:
Zdroj: The Journal of Immunology. 206:61.11-61.11
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.206.supp.61.11
Popis: At homeostasis, most Th17 cells are found in the lamina propria of the intestine, where they contribute to tissue homeostasis by inhibiting microbiota from tissue invasion and promote barrier functions. Recent studies in humans and mice have implicated intestinal Th17 cells in extra-intestinal autoimmune diseases, including multiple sclerosis, but the mechanism in which intestinal Th17 cells mediate these dichotomous functions remains unknown. Here, we combined single-cell RNA- and TCR-seq (scRNA/TCR-seq) with fate mapping of tissue Th17 cells to profile over 84,000 tissue Th17 cells and characterize their heterogeneity, plasticity, and migration at homeostasis and during CNS autoimmunity. We discovered a homeostatic Th17 cell population, that is induced by the intestinal microbiota, is present in both lymphoid organs and the intestine, and expresses IL-17. Joint scRNA- and TCR-seq showed that during EAE this homeostatic population gives rise to a pathogenic Th17 cell population, that migrates specifically through the draining lymph nodes and the spleen to the CNS, and highly expresses GM-CSF and IFNγ, but expresses little or low levels of IL-17. This conversion of homeostatic Th17 cells into encephalitogenic Th17 cells depended on IL-23R signaling. Our work characterizes Th17 heterogeneity, plasticity, and migration during homeostasis and CNS autoimmune disease, identifies a mechanism by which intestinal Th17 cells influence the generation of an autoimmune disease-inducing population, and provides further evidence for a direct relationship between the IL-17-producing and GM-CSF- and IFNγ- producing pathogenic T cells.
Databáze: OpenAIRE
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