Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit.

Rosas-Ballina M; Olofsson PS; Ochani M; Valdés-Ferrer SI; Levine YA; Reardon C; Tusche MW; Pavlov VA; Andersson U; Chavan S; Mak TW; Tracey KJ

doi:10.1126/science.1209985

Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit.

Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI ... Andersson U, Chavan S, Mak TW, Tracey KJ Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ

Science. 2011 Oct 7; 334(6052):98-101

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20 Oct 2011

Recommended

Aaron DiAntonio
F1000 Neuroscience
Washington University Medical School, St Louis, MO, USA.

New Finding, Novel Drug Target

DOI: 10.3410/f.13353011.14726198

This is an exciting study that identifies T cells as the long-sought source of acetylcholine in the vagal nerve inflammatory reflex. It has long been known that vagal stimulation to the spleen inhibits tumor necrosis factor production and that this effect requires acetylcholine. However, the vagus is adrenergic, and so the source of the acetylcholine has been a mystery.

This paper demonstrates that action potentials in the vagus regulate a class of T cells that can synthesize and release acetylcholine to mute the innate immune response. The identification of these T cells as a key component of this neural circuit may stimulate the development of novel therapies for inflammatory and autoimmune disorders.

Disclosures

None declared

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Cite this Recommendation

DiAntonio A: F1000Prime Recommendation of [Rosas-Ballina M et al., Science 2011, 334(6052):98-101]. In F1000Prime, 20 Oct 2011; DOI: 10.3410/f.13353011.14726198. F1000Prime.com/13353011#eval14726198

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24 Oct 2011

Recommended

Reina Mebius
F1000 Immunology
VU University Medical Center, Amsterdam, Netherlands.

Serge van de Pavert
F1000 Immunology
Vrije Universiteit Medical Center, Amsterdam, NH, Netherlands.

Confirmation, New Finding, Novel Drug Target

DOI: 10.3410/f.13353011.14726330

This article presents a novel way by which the nervous system influences an immune response in the spleen. Excitingly, it describes that splenic memory T lymphocytes translate signaling from nerves into an immune response.

Although the immune system is dampened by acetylcholinergic signaling through the alpha7 nicotinic acetylcholine receptor on macrophages, the authors point out that innervating nerve fibers into the spleen are instead adrenergic. In this publication, the authors showed that in vivo vagal electrical stimulation in animals or in vitro addition of norepinephrin to non-adherent spleen cells increased acetylcholine levels in either spleen or supernatant, respectively. Moreover, endotoxin-induced tumour necrosis factor (TNF) serum levels could only be lowered upon vagal stimulation in mice that contained T cells, as nude mice (devoid of T cells) did not lower TNF serum levels. Thus, these results indicated that T cells are necessary for passing on the immune response.

The authors determined that a T memory cell population synthesized acetylcholine and propose that, upon triggering of the adrenergic receptors, these memory T cells produce acetylcholine. In addition, activation of the memory T cells by CD3 beads led to more cells with a necessary enzyme for acetylcholine synthesis. Injection of sorted acetylcholinergic positive T memory cells in nude mice resulted in repression of TNF serum levels after in vivo vagal stimulation and endotoxin injection, confirming functionality of these cells.

Finally, the authors hint at a more general role of these acetylcholine-synthesizing T cells in Peyer's patches and inguinal lymph nodes. However, the heterogeneity which is seen for skin draining versus mucosal tissue draining lymph nodes suggests that cells in the various lymph nodes may respond differently and this may need further study.

Disclosures

None declared

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Cite this Recommendation

Mebius R and van de Pavert S: F1000Prime Recommendation of [Rosas-Ballina M et al., Science 2011, 334(6052):98-101]. In F1000Prime, 24 Oct 2011; DOI: 10.3410/f.13353011.14726330. F1000Prime.com/13353011#eval14726330

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08 Nov 2011

Recommended

Karsten Gronert
F1000 Immunology
University of California, Berkeley, Berkeley, CA, USA.

New Finding, Novel Drug Target

DOI: 10.3410/f.13353011.14730267

Vagus nerve activation inhibits cytokine production and regulates macrophage function in the spleen. This inflammatory reflex is protective and activated by acetylcholine. This paper unravels a long-standing mystery, namely the source of acetylcholine, which unexpectedly is memory-like T cells that are activated by nerve action potentials. This discovery has important implications for the interaction of T cells and the nervous system and regulation of immune responses.

Disclosures

None declared

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Cite this Recommendation

Gronert K: F1000Prime Recommendation of [Rosas-Ballina M et al., Science 2011, 334(6052):98-101]. In F1000Prime, 08 Nov 2011; DOI: 10.3410/f.13353011.14730267. F1000Prime.com/13353011#eval14730267

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16 Nov 2011

Recommended

Philippe Bousso
F1000 Immunology
Institut Pasteur, INSERM U668, Paris 15, France.

Jacques Deguine
F1000 Immunology
Institut Pasteur, France.

New Finding

DOI: 10.3410/f.13353011.14740119

This article is interesting because it describes the mechanism at the interface of the nervous and immune systems responsible for the previously described modulation of cytokine production by vagus nerve stimulation {1}.

Stimulation of the vagus or the splenic nerve can decrease the amount of tumour necrosis factor (TNF) produced during endotoxemia, a phenomenon termed the inflammatory reflex. However, the splenic nerve mainly utilizes norepinephrine whereas the immune cells need to respond to acetylcholine, so the mechanisms of the inflammatory reflex remained unclear.

Here, the authors demonstrate that splenic lymphocytes can produce acetlycholine upon stimulation with norepinephrine. Using a reporter for choline acetyltransferase - ChAT, a critical enzyme in acetylcholine synthesis - they showed that a population of effector memory CD4 T cells is responsible for acetylcholine production in the spleen. These ChAT+ cells are sufficient to restore the inflammatory reflex in nude mice. Furthermore, the article provides evidence that some of these T cells are located directly adjacent to splenic nerve endings and express adrenergic receptors, suggesting that they act directly downstream of nerve stimulation.

Interestingly, ChAT expression was restricted to the effector memory subset and increased after T cell stimulation. This indicates a possible link between the status of T cell responses and the efficiency of the inflammatory reflex.

References

Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.

Borovikova LV, Ivanova S, Zhang M, Yang H, ..., Wang H, Abumrad N, Eaton JW, Tracey KJ. Nature 2000 May 25; 6785(405):458-62

PMID: 10839541

Disclosures

None declared

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Cite this Recommendation

Bousso P and Deguine J: F1000Prime Recommendation of [Rosas-Ballina M et al., Science 2011, 334(6052):98-101]. In F1000Prime, 16 Nov 2011; DOI: 10.3410/f.13353011.14740119. F1000Prime.com/13353011#eval14740119

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28 Mar 2012

Recommended

Dennis Taub
F1000 Immunology
National Institute on Aging, National Institutes of Health, Baltmore, MD, USA.

Ana Lustig
F1000 Immunology
National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.

New Finding

DOI: 10.3410/f.13353011.15750059

In this article, Rosas-Ballina and colleagues describe a direct interaction between vagus nerve release of norepinephrine and acetylcholine production by memory T cells, which results in decreased tumor necrosis factor (TNF)-alpha release and, thus, an attenuated inflammatory response. This study provides an intriguing glimpse into the crosstalk between the neural and immune networks within the body and suggests the possibility of using these acetylcholine-expressing T cells for future therapeutic modulation of inflammation and autoimmunity.

Disclosures

None declared

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Taub D and Lustig A: F1000Prime Recommendation of [Rosas-Ballina M et al., Science 2011, 334(6052):98-101]. In F1000Prime, 28 Mar 2012; DOI: 10.3410/f.13353011.15750059. F1000Prime.com/13353011#eval15750059

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F1000Prime Recommendations, Dissents and Comments for [Rosas-Ballina M et al., Science 2011, 334(6052):98-101]. In F1000Prime, 20 Jun 2013; F1000Prime.com/13353011

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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.

DOI: 10.1126/science.1209985

PMID: 21921156

Abstract courtesy of PubMed: A service of the National Library of Medicine and the National Institutes of Health.

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