Cholinergic control of Th17 cell pathogenicity in experimental autoimmune encephalomyelitis

• Published in: Cell death and differentiation 2023-02, Vol.30 (2), p.407-416
• Main Authors: Nechanitzky, Robert, Nechanitzky, Duygu, Ramachandran, Parameswaran, Duncan, Gordon S., Zheng, Chunxing, Göbl, Christoph, Gill, Kyle T., Haight, Jillian, Wakeham, Andrew C., Snow, Bryan E., Bradaschia-Correa, Vivian, Ganguly, Milan, Lu, Zhibin, Saunders, Mary E., Flavell, Richard A., Mak, Tak W.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/31; 13/51; 14/63; 38/39; 38/77; 38/91; 42/35; 45/41; 631/250; 631/250/127; 631/250/256; 64/60; 692/308/1426; Acetylcholine - metabolism; Acetyltransferase; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cancer; Cell activation; Cell Biology; Cell Cycle Analysis; Cell Differentiation; Cells; Choline O-acetyltransferase; Cholinergic Agents; Cytokines; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental; Experimental allergic encephalomyelitis; Flow cytometry; Gene expression; Helper cells; Immunology; Immunomodulation; Interleukin 17; Interleukin 22; Laboratories; Life Sciences; Lymphocytes; Lymphocytes T; Medicine; Mice; Mice, Inbred C57BL; Multiple sclerosis; Multiple Sclerosis - genetics; Pathogenicity; Peptides; Stem Cells; Th17 Cells; Virulence
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-022-01092-y

Experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS) in which Th17 cells have a crucial but unclear function. Here we show that choline acetyltransferase (ChAT), which synthesizes acetylcholine (ACh), is a critical driver of pathogenicity in EAE. Mice with ChAT-deficient Th17 cells resist disease progression and show reduced brain-infiltrating immune cells. ChAT expression in Th17 cells is linked to strong TCR signaling, expression of the transcription factor Bhlhe40, and increased Il2, Il17, Il22 , and Il23r mRNA levels. ChAT expression in Th17 cells is independent of IL21r signaling but dampened by TGFβ, implicating ChAT in controlling the dichotomous nature of Th17 cells. Our study establishes a cholinergic program in which ACh signaling primes chronic activation of Th17 cells, and thereby constitutes a pathogenic determinant of EAE. Our work may point to novel targets for therapeutic immunomodulation in MS.