The study investigates the role of acetylcholine-producing T cells in the inflammatory reflex, a neural circuit that regulates cytokine production to prevent damaging inflammation. The inflammatory reflex involves vagus nerve stimulation, which inhibits tumor necrosis factor-α (TNF-α) production in the spleen through acetylcholine signaling via α7 nicotinic acetylcholine receptors on cytokine-producing macrophages. However, nerve fibers in the spleen lack the machinery to produce acetylcholine, raising the question of how this circuit terminates in cholinergic signaling. The researchers identified a population of acetylcholine-producing, memory phenotype T cells in mice that are essential for the inflammatory reflex. These T cells are required for the inhibition of cytokine production by vagus nerve stimulation. The study demonstrates that action potentials from the vagus nerve regulate T cells, which then produce acetylcholine to control innate immune responses. Key findings include the elevation of acetylcholine levels in the spleen following vagus nerve stimulation, the localization of acetylcholine-synthesizing T cells near catecholaminergic nerve endings, and the critical role of these T cells in attenuating TNF-α levels in endotoxemia. These results highlight the functional role of acetylcholine-producing memory T cells in the inflammatory reflex and suggest potential therapeutic targets for inflammatory and autoimmune diseases.The study investigates the role of acetylcholine-producing T cells in the inflammatory reflex, a neural circuit that regulates cytokine production to prevent damaging inflammation. The inflammatory reflex involves vagus nerve stimulation, which inhibits tumor necrosis factor-α (TNF-α) production in the spleen through acetylcholine signaling via α7 nicotinic acetylcholine receptors on cytokine-producing macrophages. However, nerve fibers in the spleen lack the machinery to produce acetylcholine, raising the question of how this circuit terminates in cholinergic signaling. The researchers identified a population of acetylcholine-producing, memory phenotype T cells in mice that are essential for the inflammatory reflex. These T cells are required for the inhibition of cytokine production by vagus nerve stimulation. The study demonstrates that action potentials from the vagus nerve regulate T cells, which then produce acetylcholine to control innate immune responses. Key findings include the elevation of acetylcholine levels in the spleen following vagus nerve stimulation, the localization of acetylcholine-synthesizing T cells near catecholaminergic nerve endings, and the critical role of these T cells in attenuating TNF-α levels in endotoxemia. These results highlight the functional role of acetylcholine-producing memory T cells in the inflammatory reflex and suggest potential therapeutic targets for inflammatory and autoimmune diseases.