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Update Trends in Immunology Vol.29 No.7
Letters Response
Response to Drs. Straub and Jessop
Rafael Franco1, Rodrigo Pacheco2, Carmen Lluis1, Gerard P. Ahern3 andPeta J. O’Connell4
1 IDIBAPS (Institut d’Investigacions Biomediques August Pi I Sunyer) and Department of Biochemistry and Molecular Biology,
University of Barcelona, 08028 Barcelona, Spain2 Laboratorio de Inmunogenetica, Departamento de Microbiologıa y Genetica Molecular, Facultad de Ciencias Biologicas, Pontificia
Universidad Catolica de Chile, Santiago E-8331010, Chile3 Department of Pharmacology, Georgetown University, MedDent SW401, Washington, DC 20007, USA4 BioTherapeutics Research Group, Robarts Research Institute, and the Department of Anatomy and Cell Biology, University of
Western Ontario, London, Ontario N6A 5K8, Canada
We thank Drs. Straub and Jessop for their comments andinterest in our recent paper on ‘The emergence of neuro-transmitters as immune modulators’ [1]. It has long beenappreciated and widely acknowledged that a variety ofmolecules with key functions in the neuroendocrine sys-tem, including neurotransmitters, peptides and hormones,can exert profound effects on the development and matu-ration of immune responses. The intent of our recentreview, however, was to focus on a novel concept in leu-kocyte signalling, namely neurotransmission at theimmune synapse. We welcome a vigorous discussion ofthis topic, because it is through this process that emergingparadigms are most robustly tested and further developed.
The impetus for the review article arose because ofrecent data from our laboratories that demonstrated thatdendritic cells can sequester and release neurotransmit-ters, enabling them to activate neurotransmitter receptorsexpressed by T cells [2,3]. The relevance of these newfindings, with respect to the established works ofDrs. Straub and Jessop, is evidenced for example, by thepublication of contemporaneous commentaries [4].
The objective of our review was to highlight the recentfindings in this rapidly progressing field and to discussneurotransmitter signalling at the immunological synapse.Unfortunately, limitations of spacemeant that we could notacknowledge the contributions of all authors working inclosely allied fields of neuroimmunology. Some omissionsare therefore inevitable. Where possible, we cited primaryarticles over the past 2–4 years and referenced reviewarticles for older contributions as is the convention forTrends reviews. We therefore apologize to Drs. Strauband Jessop and indeed any other authors whom we havenot been able to cite directly, but note that their work, alongwithmany relevant others is well represented in our chosenreviews.
In 1993, Rinner and Schauenstein [5] indeed reportedthat lymphocytes (not specifically T lymphocytes) possesscholine-acetyltransferase activity. In our article, we citedthe review from Kawashima and Fujii, in Japan [6], whichclearly reports earlier observations of the localization andsynthesis of acetylcholine (ACh) in human T cells, as wellas the report by Rinner et al. [7] that rat lymphocytessecrete acetylcholine depending on their differentiation
Corresponding author: Franco, R. ([email protected]).
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and activation. In our opinion, the citations in our revieware appropriate, as is the reference to this excellent review[6].
Our statement related to corticosteroids and catechol-amines refers to immune regulation by these compoundssecreted from the adrenal gland and sympathetic nerves,respectively. We regret any confusion caused. We statedthat catecholamines ‘generally’ exert an immunosuppres-sive effect. This is certainly not a categorical assertion, andwe specifically added ‘Interestingly, there are exceptions tothis general trend’. Indeed, the recent discovery that dopa-mine downregulates the function of regulatory T cells addsfurther complexity to this issue [8].
The word ‘spleen’ appears only once in our review, andwe did not explicitly state that the spleen is innervated;furthermore, we are aware this remains controversial inmammals. In our review, we reported on findings that Tcells synthesize and release ACh upon activation [5,6]. Asstated, ‘activation [of T cells] typically occurs in the para-cortex of lymph nodes, or the periarteriolar lymphoidsheath of the spleen.’ ACh released from these activatedT cells might lead to high local concentrations of ACh andautocrine/paracrine signalling via muscarinic or nicotinicACh receptors expressed on the surface of T cells. Further-more, lymph nodes have an additional source of ACh fromnerve terminals, which may also contribute to cholinergicsignalling in T cells.
Similarly, our review of recent findings on the role of5-HT (serotonin) in T-cell function has also been miscon-strued by Drs. Straub and Jessop. In the original context ofour review, we highlight the recent novel finding thatT cells can synthesize serotonin [9] and discuss the specificreceptor-mediated signalling pathways that have beendefinitively identified in T cells [1,9]. In our opinion, thesedata constitute new, relevant and direct evidence thatserotonin is important for T-cell function.
Drs. Straub and Jessop mention that opioid productionby immune cells in the vicinity of nerve fibres can affectpain reception pathways [10]; however, the concept ofvolume transmission is not explicitly outlined in thispaper. ‘Wiring transmission’ and ‘volume transmission’are terms coined in 1986 by Agnati et al. to distinguishlong-range (volume) from short-range (wiring) neurotrans-mission ([11], reviewed in [12]). Wiring transmissiondescribes the neurotransmitter-induced activation of
Update Trends in Immunology Vol.29 No.7
nearby synaptic receptors. By contrast, volume trans-mission describes the ‘spillover’ activation of extrasynapticreceptors. We used these terms to illustrate that similarmechanisms can occur in both the nervous and immunesystems. For neuroimmunologists, we feel that these arehelpful and interesting analogies to make.
As evidenced in our review, the topic of neurotransmit-ter synthesis and signalling in the immune system is arapidly developing field of neuroimmunology. This discus-sion is proof that there is a real vitality and excitement inthe field, and we appreciate the continuing debate.
References1 Franco, R. et al. (2007) The emergence of neurotransmitters as immune
regulators. Trends Immunol. 28, 400–4072 O’Connell, P.J. et al. (2006) A novel form of immune signaling revealed
by transmission of the inflammatory mediator serotonin betweendendritic cells and T cells. Blood 107, 1010–1017
3 Pacheco, R. et al. (2006) Glutamate released by dendritic cells as a novelmodulator of T cell activation. J. Immunol. 177, 6695–6704
4 Gordon, J. and Barnes, N.M. (2007) Serotonin: a real blast for T cells.Blood 109, 3130–3131
5 Rinner, I. and Schauenstein, K. (1993) Detection of choline-acetyltranferase in lymphocytes. J. Neurosci. Res. 35, 188–191
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6 Kawashima, K. and Fujii, T. (2003) The lymphocytic cholinergic systemand its biological function. Life Sci. 72, 2101–2109
7 Rinner, I. et al. (1998) Rat lymphocytes produce and secreteacetylcholine in dependence of differentiation and activation.J. Neuroimmunol. 81, 31–37
8 Cosentino, M. et al. (2007) Human CD4+CD25+ regulatory T cellsselectively express tyrosine hydroxylase and contain endogenouscatecholamines subserving an autocrine-paracrine inhibitoryfunctional loop. Blood 109, 632–642
9 Leon-Ponte, M. et al. (2007) Serotonin provides an accessory signal toenhance T-cell activation by signaling through the 5-HT7 receptor.Blood109, 3139–3146
10 Stein, C. et al. (1990) Opioids from immunocytes interact withreceptors on sensory nerves to inhibit nociception in inflammation.Proc. Natl. Acad. Sci. U. S. A. 87, 5935–5939
11 Agnati, L.F. et al. (1986) A correlation analysis of the regional distri-bution of central enkephalin and beta-endorphin immunoreactiveterminals and of opiate receptors in adult and old male rats. Evidencefor the existence of two main types of communication in the centralnervous system: the volume transmission and the wiring transmission.Acta Physiol. Scand. 128, 201–207
12 Zoli, M. et al. (1999) Volume transmission in the CNS and its relevancefor neuropsychopharmacology. Trends Pharmacol. Sci. 20, 142–150
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