Cholinergic control of Th17 cell pathogenicity in experimental autoimmune encephalomyelitis

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 TGF beta, 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.

Automated summary

Choline acetyltransferase (ChAT) plays a critical role in the pathogenicity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). ChAT-deficient Th17 cells in mice resist disease progression and show reduced brain-infiltrating immune cells. ChAT expression in Th17 cells is associated with TCR signaling, Bhlhe40 transcription factor, and increased mRNA levels of Il2, Il17, Il22, and Il23r.