Lymphocyte-derived ACh regulates local innate but not adaptive immunity

Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1410-5. doi: 10.1073/pnas.1221655110. Epub 2013 Jan 7.

Abstract

Appropriate control of immune responses is a critical determinant of health. Here, we show that choline acetyltransferase (ChAT) is expressed and ACh is produced by B cells and other immune cells that have an impact on innate immunity. ChAT expression occurs in mucosal-associated lymph tissue, subsequent to microbial colonization, and is reduced by antibiotic treatment. MyD88-dependent Toll-like receptor up-regulates ChAT in a transient manner. Unlike the previously described CD4(+) T-cell population that is stimulated by norepinephrine to release ACh, ChAT(+) B cells release ACh after stimulation with sulfated cholecystokinin but not norepinephrine. ACh-producing B-cells reduce peritoneal neutrophil recruitment during sterile endotoxemia independent of the vagus nerve, without affecting innate immune cell activation. Endothelial cells treated with ACh in vitro reduced endothelial cell adhesion molecule expression in a muscarinic receptor-dependent manner. Despite this ability, ChAT(+) B cells were unable to suppress effector T-cell function in vivo. Therefore, ACh produced by lymphocytes has specific functions, with ChAT(+) B cells controlling the local recruitment of neutrophils.

MeSH terms

  • Acetylcholine / biosynthesis*
  • Adaptive Immunity / physiology*
  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Choline O-Acetyltransferase / genetics
  • Choline O-Acetyltransferase / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Female
  • Immunity, Innate / physiology*
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism*
  • Lymphoid Tissue / immunology
  • Lymphoid Tissue / metabolism
  • Lymphoid Tissue / microbiology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Metagenome / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Neuroimmunomodulation
  • Pregnancy
  • Receptors, Neurotransmitter / immunology
  • Receptors, Neurotransmitter / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Toll-Like Receptors / metabolism

Substances

  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Neurotransmitter
  • Recombinant Fusion Proteins
  • Toll-Like Receptors
  • Choline O-Acetyltransferase
  • Acetylcholine