title: Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28.
abstract: Productive T-cell immunity requires both the activation and the migration of specific T cells to the antigenic tissue. The costimulatory molecule CD28 plays an essential role in the initiation of T-cell-mediated immunity. We investigated the possibility that CD28 may also regulate migration of primed T cells to target tissue. In vitro, CD28-mediated signals enhanced T-cell transendothelial migration, integrin clustering, and integrin-mediated migration. In vivo, T cells bearing a mutation in the CD28 cytoplasmic domain, which abrogates PI3K activation, displayed normal clonal expansion but defective localization to antigenic sites following antigenic rechallenge. Importantly, antibody-mediated CD28 stimulation led to unregulated memory T-cell migration to extra-lymphoid tissue, which occurred independently of T-cell receptor (TCR)-derived signals and homing-receptor expression. Finally, we provide evidence that CD28- and CTLA-4-mediated signals exert opposite effects on T-cell trafficking in vivo. These findings highlight a novel physiologic function of CD28 that has crucial implications for the therapeutic manipulation of this and other costimulatory molecules.
authors.affiliation: Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mirenda
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Jarmin
authors.forename: Rachel
authors.initials: R
authors.lastname: David
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
authors.forename: Diane
authors.initials: D
authors.lastname: Scott
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lechler
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Federica M
authors.initials: FM
authors.lastname: Marelli-Berg
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000941:Antigens; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D060908:CTLA-4 Antigen; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017354:Point Mutation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology*
chemical_list: D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D016023:Integrins; C111390:OVA 323-339; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases