Mobilisation of specific T cells from lymph nodes in contact sensitivity requires substance P Andrew J. Shepherd a , Lorna J. Beresford a , Eric B. Bell b , Jaleel A. Miyan a, * a Faculty of Life Sciences, Division of Neurosciences, The University of Manchester, Jackson’s Mill, Sackville Street, PO Box 88 Manchester, M60 1QD, UK b Division of Immunology, The University of Manchester, UK Received 2 March 2005; accepted 18 April 2005 Abstract Capsaicin-mediated depletion of neuropeptides in the skin was previously shown to abolish a dinitrocholorobenzene (DNCB)-induced contact sensitivity (CS) response. To understand the basis for this disruption, we explored whether nerve fibres innervating the draining lymph node (LN) could be involved. As expected, removal of the draining LN after DNCB sensitisation abolished the CS response. Furthermore, the CS response could be abolished by destroying the nerve fibres in the draining LN and could be restored by providing the LN with the neuropeptide substance P. The size of the CS response restored by substance P was dose dependent. The response was also inhibited by exposing the lymph node to a neurokinin-1 receptor antagonist which blocks binding of substance P. The results suggest that an afferent signal from the skin via the sympathetic arm of the central nervous system evokes an efferent signal to the LN which combines to regulate the CS response. The efferent signal may serve to control or release from the LN primed effector lymphocytes into the circulation. D 2005 Elsevier B.V. All rights reserved. Keywords: Nerve fibres; Contact sensitivity; Lymph node; Capsaicin; Substance P 1. 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 vaso- dilatation, adhesion molecule expression, leukocyte activa- tion, 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 (epider- mal 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 naı ¨ve CD4 + T lymphocytes (sensitisation). CD4 + T cells are required to induce and to adaptively transfer the CS response to naı ¨ve 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 (g- 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 0165-5728/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2005.04.008 * Corresponding author. Tel.: +44 161 306 4205; fax: +44 161 236 0409. E-mail address: j.miyan@manchester.ac.uk (J.A. Miyan). Journal of Neuroimmunology 164 (2005) 115 – 123 www.elsevier.com/locate/jneuroim