A neural circuit involving acetylcholine-producing T cells in the spleen regulates immune responses through the vagus nerve. The study identifies a subset of memory T cells that synthesize acetylcholine and are essential for the inflammatory reflex, a neural pathway that inhibits cytokine production. These T cells, which express the enzyme choline acetyltransferase (ChAT), are located in the white pulp of the spleen and are in close proximity to splenic nerve fibers. When the vagus nerve is stimulated, action potentials travel to these T cells, prompting them to release acetylcholine, which then interacts with α7 nicotinic acetylcholine receptors on macrophages to suppress cytokine production, particularly tumor necrosis factor-α (TNF-α). This process is critical for controlling inflammation and maintaining homeostasis. The study shows that T cells are necessary for the inflammatory reflex, as their absence impairs the ability of the vagus nerve to reduce TNF-α levels during endotoxemia. Using genetically modified mice, researchers confirmed that ChAT-expressing T cells are a small subset of memory T cells and that their activation enhances ChAT expression and acetylcholine release. These T cells are also present in lymph nodes and Peyer's patches, suggesting a broader role in immune regulation. The findings indicate that acetylcholine-synthesizing T cells are integral to the neural control of innate immune responses, offering new therapeutic targets for inflammatory and autoimmune diseases.A neural circuit involving acetylcholine-producing T cells in the spleen regulates immune responses through the vagus nerve. The study identifies a subset of memory T cells that synthesize acetylcholine and are essential for the inflammatory reflex, a neural pathway that inhibits cytokine production. These T cells, which express the enzyme choline acetyltransferase (ChAT), are located in the white pulp of the spleen and are in close proximity to splenic nerve fibers. When the vagus nerve is stimulated, action potentials travel to these T cells, prompting them to release acetylcholine, which then interacts with α7 nicotinic acetylcholine receptors on macrophages to suppress cytokine production, particularly tumor necrosis factor-α (TNF-α). This process is critical for controlling inflammation and maintaining homeostasis. The study shows that T cells are necessary for the inflammatory reflex, as their absence impairs the ability of the vagus nerve to reduce TNF-α levels during endotoxemia. Using genetically modified mice, researchers confirmed that ChAT-expressing T cells are a small subset of memory T cells and that their activation enhances ChAT expression and acetylcholine release. These T cells are also present in lymph nodes and Peyer's patches, suggesting a broader role in immune regulation. The findings indicate that acetylcholine-synthesizing T cells are integral to the neural control of innate immune responses, offering new therapeutic targets for inflammatory and autoimmune diseases.