Mobilisation of specific T cells from lymph nodes in contact sensitivity requires substance P
Introduction
The skin is recognised as a primary host defence mechanism and it is not surprising to find it invested with an extensive nerve supply to monitor this important barrier and mediate rapid responses to host challenge. Nerve fibres associated with the skin may be viewed as a primary response pathway in the innate immune response to external agents (Ansel, 2001) releasing, as well as stimulating the release of, proinflammatory cytokines involved in vasodilatation, adhesion molecule expression, leukocyte activation, chemotaxis and cell proliferation (Ansel, 2001, Ansel et al., 1997). By their nature, these consequences of neural activation interface with the immune system at a number of different levels including cutaneous dendritic cells (epidermal Langerhans cells), mast cells, keratinocytes and the endothelium of capillaries.
Epidermal Langerhans cells mediate contact sensitivity (CS) responses to hapten antigens by internalising the hapten molecules, migrating via the draining lymphatic vessels to paracortical areas of regional lymph nodes (LNs), and there presenting hapten–MHCII complexes to naïve CD4+ T lymphocytes (sensitisation). CD4+ T cells are required to induce and to adaptively transfer the CS response to naïve recipients (Bunce and Bell, 1997, Gautam et al., 1991, Kondo et al., 1996, Miller and Jenkins, 1985). CD4+ together with CD8+ T cells mediate the secondary response by inducing Th 1-type cytokine release (γ-interferon) in the skin at the point of second exposure (challenge) to hapten (Gocinski and Tigelaar, 1990, Xu et al., 1996). The hypersensitivity response on secondary exposure is therefore a product of a form of “learning” by a mechanism that links anatomically distant sites. This could involve mobile cells, soluble chemical messengers or pathways mediated by another system of the body, specifically the nervous system (Beresford et al., 2004, Downing and Miyan, 2000).
Cutaneous nerve fibres are associated with Langerhans cells (Asahina et al., 1995b, Crivellato et al., 1994, Gaudillere et al., 1996, Hosoi et al., 1993, Misery, 1996, Muller, 2000) and mast cells (Blennerhassett and Bienenstock, 1998, Blennerhassett et al., 1991, Jarvikallio et al., 2003) that express neuropeptide receptors (Staniek et al., 1999, Staniek et al., 1997, Torii et al., 1997c), mediating the release of proinflammatory cytokines (Auais et al., 2003, Belvisi, 2003, Saade et al., 2002) and neurogenic inflammation. These nerve fibres classically serve sensory functions involved in nociception (Belvisi, 2003, Lin et al., 2003, Sumikura et al., 2003) and contain the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). CGRP inhibits both antigen presentation by Langerhans cells (Asahina et al., 1995c, Hosoi et al., 1993) and the contact sensitivity (CS) response (Asahina et al., 1995a, Torii et al., 1997a), a finding attributable to down-regulation of MHCII and B7-2 (CD86) expression (Carucci et al., 2000) and induction of IL-12 expression (Torii et al., 1997b). CGRP induces the production and release of IL-10 by mast cells (Niizeki et al., 1997) and suppresses the expression and release of IL-2 by T lymphocytes (Wang et al., 1992). Furthermore, CGRP inhibits the proliferation of both T (Boudard and Bastide, 1991, Wang et al., 1994) and B (McGillis et al., 1995) lymphocytes. SP enhances the CS response through indirect pathways (Niizeki et al., 1999), and potentially by controlling the release of both mature and blast CD4+ T lymphocytes from LNs into efferent lymphatic vessels (Moore et al., 1989, Moore et al., 1990). SP also modulates adhesion molecule levels on endothelial cells (Lindsey et al., 2000, Quinlan et al., 1999a, Quinlan et al., 1999b, Quinlan et al., 1998) and lymphocyte adhesion as a result (Levite, 2000, Levite et al., 1998). In addition, SP acts directly on immune cells to stimulate the secretion of chemokines (Lotz et al., 1988, Paegelow et al., 1989) and can induce mast cell degranulation and TNF-α release at nanomolar concentrations (Ansel et al., 1993). Capsaicin-mediated deletion of these peptidergic nerve fibres results in abolition of the CS response (Beresford et al., 2004), a reduction of vasodilation and plasma extravasation, as well as an 80% reduction in antibody response to sheep red blood cells injected subcutaneously, effects that are reversed by subcutaneous infusion of SP (Helme et al., 1987). Thus, CGRP and substance P, co-localised in the same nerve fibres and present in LNs and skin, are likely to be involved in the control and coordination of immune responses, including conditions of abnormal function such as dermatitis and psoriasis (Darsow and Ring, 2001, Hsieh et al., 1996, Jarvikallio et al., 2003, Kinkelin et al., 2000, Misery, 1997, Niizeki et al., 1997, Scholzen et al., 1998, Staniek et al., 1998). In this paper we report experiments that demonstrate a critical role for substance P in a well-characterised CS immune response.
Section snippets
Mice
All experiments were sanctioned by the Home Office animal procedures inspectorate. Outbred CD1 mice 6–8 weeks of age were purchased from Harlan UK Ltd (Bicester, UK) and maintained on a 12 h : 12 h light : dark cycle beginning at 08:00 with free access to food and water. All procedures were performed between 10:00 am and 1:00 pm.
Cutaneous denervation
Mice were anaesthetised with a 2% halothane in nitrous oxide–oxygen gas mixture and maintained under surgical anaesthesia with 0.5–1.0% halothane in nitrous oxide–oxygen.
Results
Our previous study (Beresford et al., 2004) showed that deletion of nerve fibres in the skin did not prevent the appearance of antigen containing cells in the draining LN but did prevent the normal development of a CS response induced by DNCB. This occurred whether the nerve fibres were deleted at the sensitisation site (abdomen or ear), the challenge site (ear) or both. Furthermore, our studies showed that denervation did not prevent antigen-carrying Langerhans cells from migrating to the
Discussion
The present study suggests that nerve fibres may have a more direct influence on the immune system than generally assumed. Although the role of nerve fibres within the skin in CS and other conditions has long been recognised by dermatologists, no attempt to link cutaneous signals to the central nervous system has been explored before by the methods used here.
In earlier investigations, we showed neural control of the bone marrow (Afan et al., 1997, Broome and Miyan, 2000, Broome et al., 2000),
Acknowledgements
We are grateful to the Medical Research Council and the Wellcome Trust for support of this work. We thank Nick Ritchie, Janet Wilson-Walsh and Pauline Symonds for technical assistance.
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