title: T-cell receptor- and CD28-induced Vav1 activity is required for the accumulation of primed T cells into antigenic tissue.
abstract: Localization of primed T cells to antigenic tissue is essential for the development of effective immunity. Together with tissue-selective homing molecules, T-cell receptor (TCR)- and CD28-mediated signals have been shown to promote transendothelial migration of specific T cells into nonlymphoid antigen-rich tissue. However, the cellular and molecular requirements for T-cell accumulation to target tissue following their recruitment are largely undefined. The guanine nucleotide exchange factor (GEF) Vav1 has an integral role in coupling TCR and CD28 to signaling pathways that regulate T-cell activation and migration. Here, we have investigated the contribution of TCR- and CD28-induced Vav1 activity to the trafficking and localization of primed HY-specific CD4(+) T cells to antigenic sites. Severe migratory defects displayed by Vav1(-/-) T cells in vitro were fully compensated by a combination of shear flow and chemokines, leading to normal recruitment of Vav1(-/-) T cells in vivo. In contrast, Vav1(-/-) T-cell retention into antigen-rich tissue was severely impaired, reflecting T cells' inability to engage in sustained TCR- and CD28-mediated interactions with tissue-resident antigen-presenting cells (APCs). This novel function of APC-induced, and TCR- and CD28-mediated Vav1 activity in the regulation of effector T-cell immunity highlights its potential as a therapeutic target in T cell-mediated tissue damage.
authors.affiliation: Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: David
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Ivetic
authors.forename: Aya
authors.initials: A
authors.lastname: Takesono
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Ridley
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chai
authors.forename: Victor L
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: Federica M
authors.initials: FM
authors.lastname: Marelli-Berg
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D002450:Cell Communication / Q000502:physiology*; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D005260:Female; D007111:Immunity, Cellular / Q000502:physiology; D008213:Lymphocyte Activation / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D018925:Chemokines; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse