Functions of acetylcholine-producing lymphocytes in immunobiology

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Highlights

  • Cholinergic signals regulate inflammation and vascular function.

  • ChAT+ T and B cells have the capacity to biosynthesize and release acetylcholine.

  • ChAT+ T cells regulate immune responses and viral clearance.

Recent advances in neuroscience and immunology have shown that cholinergic signals are vital in the regulation of inflammation and immunity. Choline acetyltransferase+ (ChAT+) lymphocytes have the capacity to biosynthesize and release acetylcholine, the cognate ligand for cholinergic receptors. Acetylcholine-producing T cells relay neural signals in the ‘inflammatory reflex’ that regulate cytokine release in spleen. Mice deficient in acetylcholine-producing T cells have increased blood pressure, show reduced local vasodilatation and viral control in lymphocytic choriomeningitis virus infection, and display changes in gut microbiota compared with littermates. These observations indicate that ChAT+ lymphocytes play physiologically important roles in regulation of inflammation and anti-microbial defense. However, the full scope and importance of ChAT+ lymphocytes in immunity and vascular biology remains to be elucidated. Here, we review key findings in this emerging area.

Introduction

Acetylcholine is a key neurotransmitter of cholinergic nerves in animals, but acetylcholine is found across many systems, including in unicellular organisms, bacteria and plants. Measurable levels of acetylcholine have been reported in a range of different tissues, and cognate cholinergic receptors for acetylcholine are expressed by many cell types and across organs inside and outside of the nervous system [1, 2, 3, 4]. The cellular and synaptic actions of acetylcholine are relatively well understood in the context of nervous and musculoskeletal systems, but our mechanistic understanding of extra-neuronal cholinergic signals is much more limited.

Recent developments in neuroscience and immunology show that cholinergic signals are vital in the regulation of inflammation and immunity. Landmark discoveries by the Watkins, Niijima, and Tracey labs revealed that elevated cytokine levels in the periphery cause signals in the cholinergic vagus nerve that promote fever, and elicit motor signals to the spleen that can regulate cytokine release in inflammation [5, 6, 7]. These insights led to the definition of the ‘inflammatory reflex’, a concept that has propelled research on neural control of inflammation [8,9]. Subsequent work showed that the cholinergic α7 nicotinic acetylcholine receptor subunit (Chrna7) in immune cells, previously primarily studied in the nervous system, is essential for neural reflex regulation of cytokines in systemic inflammation, for example release of pro-inflammatory cytokines from macrophages [10, 11, 12, 13, 14, 15, 16, 17, 18]. Other cholinergic receptors also regulate immune responses. For example, activation of nicotinic or muscarinic acetylcholine receptors on T cells was reported to promote Th1 differentiation or Th2/Th17 differentiation, respectively [19]. The discovery that lymphocytes have the capacity to provide the cognate ligand for cholinergic receptors by biosynthesizing and releasing acetylcholine have revealed additional modes of immune cell communication, but much of this work is only in its infancy. Here, we review known functions of acetylcholine-producing lymphocytes.

Section snippets

Lymphocyte biosynthesis and release of acetylcholine

Acetylcholine is most well known as a principal neurotransmitter released in quanta under the control of action potentials in cholinergic nerves. Most of our understanding of acetylcholine biosynthesis and release is derived from studies of neurons, and knowledge of the implications of lymphocyte acetylcholine synthesis is limited. Choline acetyltransferase (ChAT) catalyzes acetylcholine biosynthesis from the precursors acetyl-coenzyme A (acetyl-CoA) and choline. Choline can be synthesized or

Acetylcholine-producing ChAT+ T cells

Discoveries over the last decade have revealed unexpected roles for ChAT+ T cells, including the regulation of cytokine release, blood pressure and in regulating leukocyte tissue entry in infection. Appreciating the local and systemic effects of leukocyte cholinergic signaling in infection and autoimmunity could perhaps help identify new treatment targets in inflammatory diseases [38, 39, 40].

ChAT+ B cell biology

Acquired immunity to foreign pathogens critically depends on functional B cells that develop in the bone marrow, in contrast to T lymphopoiesis that is largely restricted to the thymus in mammals. Although T cells have been the most widely studied lymphocyte population with regards to ChAT expression, ChAT+ B cells have been detected in several studies. There is limited understanding of regulation of ChAT expression and activity in B cells, but there are reports that TLR ligands (CpG, TLR2

Conclusion

In summary, the capacity of some lymphocyte subpopulations to express ChAT and biosynthesize acetylcholine has been known for decades. Only recently have distinct functional capacities of acetylcholine-producing primary lymphocytes been defined. Although available data are limited, ChAT+ T cells are essential for regulation of systemic release of pro-inflammatory cytokines by the inflammatory reflex [32], involved in blood pressure regulation [51], required for optimal anti-viral defense in

Conflict of interest statement

SM, LT, and VSS have no conflicts of interest to declare relative to this manuscript. PSO is a co-founder and shareholder of Emune AB and ChAT Therapeutics.

Acknowledgements

The work was funded by grants to PSO from the Knut and Alice Wallenberg Foundation, the Swedish Medical Council and the Stockholm Region (ALF).

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