Acetylcholine-producing T cells augment innate immune-driven colitis but are redundant in T cell-driven colitis

Clinical trials suggest that vagus nerve stimulation presents an alternative approach to classical immune suppression in Crohn's disease. T cells capable of producing acetylcholine (ChAT⁺ T cells) in the spleen are essential mediators of the anti-inflammatory effect of vagus nerve stimulation. Besides the spleen, ChAT⁺ T cells are found abundantly in Peyer's patches of the small intestine. However, the role of ChAT⁺ T cells in colitis pathogenesis is unknown. Here, we made use of CD4^creChAT^fl/fl mice (CD4ChAT^-/- mice) lacking ChAT expression specifically in CD4⁺ T cells. Littermates (ChAT^fl/fl mice) served as controls. In acute dextran sulfate sodium (DSS)-induced colitis (7 days of 2% DSS in drinking water), CD4ChAT^-/- mice showed attenuated colitis and lower intestinal inflammatory cytokine levels compared with ChAT^fl/fl mice. In contrast, in a resolution model of DSS-induced colitis (5 days of 2% DSS followed by 7 days without DSS), CD4ChAT^-/- mice demonstrated a worsened colitis recovery and augmented colonic histological inflammation scores and inflammatory cytokine levels as compared with ChAT^fl/fl mice. In a transfer colitis model using CD4⁺CD45RB^high T cells, T cells from CD4ChAT^-/- mice induced a similar level of colitis compared with ChAT^fl/fl T cells. Together, our results indicate that ChAT⁺ T cells aggravate the acute innate immune response upon mucosal barrier disruption in an acute DSS-induced colitis model, whereas they are supporting the later resolution process of this innate immune-driven colitis. Surprisingly, ChAT expression in T cells seems redundant in the context of T cell-driven colitis.NEW & NOTEWORTHY By using different mouse models of experimental colitis, we provide evidence that in dextran sulfate sodium-induced colitis, ChAT⁺ T cells capable of producing acetylcholine worsen the acute immune response, whereas they support the later healing phase of this innate immune-driven colitis.