title: Blocking development of a CD8+ T cell response by targeting lymphatic recruitment of APC.
abstract: 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 F(5) 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.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Denise
authors.initials: D
authors.lastname: Teoh
authors.forename: Louise A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Tomas
authors.initials: T
authors.lastname: Hanke
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: David G
authors.initials: DG
authors.lastname: Jackson
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005434:Flow Cytometry; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D042601:Lymphatic Vessels / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology*; D014777:Virus Diseases / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000956:Antigens, Viral; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1