Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit

TLDR

Neural circuits, such as the vagus nerve inflammatory reflex, suppress cytokine production by delivering acetylcholine to macrophages via α7 nicotinic receptors. The study seeks to determine how the vagus nerve circuit achieves cholinergic signaling despite spleen nerve fibers lacking acetylcholine‑synthesizing enzymes. The authors discovered that memory‑phenotype T cells in the spleen produce acetylcholine, are essential for vagus‑nerve‑mediated cytokine inhibition, and thus mediate the inflammatory reflex.

Abstract

Neural circuits regulate cytokine production to prevent potentially damaging inflammation. A prototypical vagus nerve circuit, the inflammatory reflex, inhibits tumor necrosis factor-α production in spleen by a mechanism requiring acetylcholine signaling through the α7 nicotinic acetylcholine receptor expressed on cytokine-producing macrophages. Nerve fibers in spleen lack the enzymatic machinery necessary for acetylcholine production; therefore, how does this neural circuit terminate in cholinergic signaling? We identified an acetylcholine-producing, memory phenotype T cell population in mice that is integral to the inflammatory reflex. These acetylcholine-producing T cells are required for inhibition of cytokine production by vagus nerve stimulation. Thus, action potentials originating in the vagus nerve regulate T cells, which in turn produce the neurotransmitter, acetylcholine, required to control innate immune responses.