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Blocking Development of a CD8⁺ T Cell Response by Targeting Lymphatic Recruitment of APC¹

Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom

Generating a protective immune response to viral infection is known to depend upon the priming and clonal expansion of virus-specific CD8⁺ T cells by Ag-loaded dendritic cells (DC) within secondary lymphoid tissue. However, the actual initiation of the response involves critical upstream events that control the recruitment of mature Ag-charged DC from the periphery via afferent lymphatics, events that are still only partly understood. Recent evidence has revealed that transmigration of lymphatic endothelium by DC is regulated by the adhesion molecules ICAM-1 and VCAM-1 both in vitro and in vivo. These findings imply that lymphatic entry may be an important rate-limiting step in primary immunity and a possible target for immune intervention. In this study, we have explored such possibilities using an F₅ TCR-transgenic mouse model to assess the contribution of lymphatic cell adhesion molecules in the CD8⁺ T cell response to influenza virus nucleoprotein (NP). We show for the first time that immunization with ICAM-1- and VCAM-1-blocking mAbs can impair the T cell response in lymph node-draining sites of dermally administered nucleoprotein vaccine (MVA.HIVA.NP) by targeting lymphatic uptake of Ag-loaded DC ahead of other cell adhesion molecule-dependent events. These results reveal lymphatic entry as an important step that may be rate limiting in the development of immunity and reconfirm its potential as a target for localized immunotherapy in inflammation and tissue rejection.

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 Unit funding from the U.K. Medical Research Council.

² D.T. and L.A.J. contributed equally to this work.

³ Current address: Singapore Institute for Clinical Sciences, BMRC Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609.

⁴ Address correspondence and reprint requests to Dr. David G. Jackson, Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, U.K. E-mail address: djackson{at}hammer.imm.ox.ac.uk

⁵ Abbreviations used in this paper: DC, dendritic cell; CAM, cell adhesion molecule; HIVA, human immunodeficiency virus A; MVA, modified vaccinia Ankara; NP, nucleoprotein; HEV, high endothelial venule.

⁶ The online version of this article contains supplemental material.