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In Vivo Signaling through the Neurokinin 1 Receptor Favors Transgene Expression by Langerhans Cells and Promotes the Generation of Th1- and Tc1-Biased Immune Responses¹

Alicia R. Mathers^*,, Olga A. Tckacheva^*,, Brian M. Janelsins^*,, William J. Shufesky^,, Adrian E. Morelli^, and Adriana T. Larregina^2,*,

^* Department of Dermatology, Department of Immunology, Thomas E. Starzl Transplantation Institute, and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

The proinflammatory capacities of the skin and the presence of high numbers of resident dendritic cells (DCs) constitute an ideal microenvironment for successful immunizations. Regardless of the ability of DCs to respond to local inflammatory signals in an immunostimulatory fashion, the immune functions of skin-resident DCs remain controversial, and epidermal Langerhans cells (LCs) have been referred to recently as anti-inflammatory/protolerogenic APCs. Substance P (SP), released by skin nerve fibers, is a potent proinflammatory neuropeptide that favors development of skin-associated cellular immunity. SP exerts its proinflammatory functions by binding with high affinity to the neurokinin 1 receptor (NK1R). In this study, we tested whether signaling skin cells via the NK1R promotes humoral and cellular immunity during skin genetic immunizations. We used the gene gun to deliver transgenic (tg) Ag to the skin of C57BL/6 mice and the selective NK1R agonist [Sar⁹Met (O₂) ¹¹]-SP as a potential proinflammatory Th1-biasing adjuvant. Our strategy expressed tg Ag exclusively in the epidermis and induced a preferential migration of activated LCs to skin-draining lymph nodes. Local administration of the NK1R agonist during skin genetic immunizations increased significantly the expression of tg Ag by a mechanism involving the translocation of NF-B into the nuclei of cutaneous DCs homing to skin-draining lymph nodes. Importantly, our immunization approach resulted in Th1 and T cytotoxic (CTL)-1 bias of effector T cells that supported cellular and Ab-mediated immune responses. We demonstrate that signaling skin cells via the NK1R provides the adjuvant effect which favors the immunostimulatory functions of LCs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 CA100893 (to A.T.L.) and R01 HL077545 and R01 HL075512 (to A.E.M.), and T32CA82084 fellowship (to A.R.M.).

² Address correspondence and reprint requests to Dr. Adriana T. Larregina, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail address: adrianal{at}pitt.edu

³ Abbreviations used in this paper: Tc1, T cytotoxic (CTL)-1; BMDC, bone marrow-derived DC; DC, dendritic cell; DDC, dermal DC; DTH, delayed-type hypersensitivity; EGFP, enhanced GFP; GG, gene gun; i.d., intradermal(ly); LC, Langerhans cell; LN, lymph node; Luc, luciferase; NK1R, neurokinin 1 receptor; pDNA, plasmid DNA; PMN, polymorphonuclear granulocyte; RLU, relative luminic unit; RT, room temperature; sDLN, skin-draining LN; %SCL, percentage of specific cell lysis; SP, substance P; tg, transgenic.

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