title: Differential regulatory effects of intercellular adhesion molecule-1 on costimulation by the CD28 counter-receptor B7.
abstract: Although ligation of the CD3/TCR complex initiates an activation signal in T cells, additional costimulatory signals generated during cell-to-cell interactions with APC transduced via ligation of CD11a/CD18 and CD28 by their specific counter-receptor intercellular adhesion molecule (ICAM)-1 and B7, respectively, are required for optimal T cell proliferation and cytokine synthesis. Using soluble IgC gamma 1 fusion proteins of these costimulatory counter-receptors, we have recently shown that unactivated resting CD4+ T cells and Ag-primed CD4+ T cells differ in their response to the costimulation by ICAM-1 and B7. Preferential proliferative responses of resting T and Ag-primed T cells to ICAM-1 and B7, respectively, prompted us to speculate that ICAM-1-induced signals may regulate coupling of the CD28 signaling pathway. Furthermore, both B7 and ICAM-1 are co-expressed on APC and thus, may co-regulate activation-driven maturation of T cells. In this study, we have examined regulatory effects of IgC gamma 1 fusion proteins of B7, ICAM-1, and ICAM-2 (a homologue of ICAM-1) on each other's costimulation. We first demonstrate that TCR-directed costimulation of resting CD4+ T cells with ICAM-1 (ICAM-1 priming) but not ICAM-2 induces increased responsiveness to B7. Priming of CD4+ T cells with ICAM-1 induced higher expression of both CD18 and CD28 than that with either B7 or ICAM-2. Cross-linking of CD28 induced faster and significantly higher cytoplasmic free calcium mobilization response in ICAM-1-primed CD4+ T cells than in resting, B7-primed, or ICAM-2-primed CD4+ T cells. B7 synergized with ICAM-1 but not ICAM-2 to augment proliferative responses of not only resting CD4+ T cells but also those that had been primed with either ICAM. Unlike resting or ICAM-2-primed CD4+ T cells, ICAM-1-primed CD4+ T cells efficiently proliferated in response to the synergistic costimulation of B7 and ICAM-2. In contrast, both ICAM-1 and ICAM-2 inhibit B7-driven proliferation of Ag-primed CD4+ T cells. Thus, B7 and ICAM-1 exert contrasting regulatory effects on the proliferation of CD4+ T cells depending on their state of activation-induced maturation.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
authors.forename: N K
authors.initials: NK
authors.lastname: Damle
authors.forename: K
authors.initials: K
authors.lastname: Klussman
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: A
authors.initials: A
authors.lastname: Aruffo
authors.forename: J A
authors.initials: JA
authors.lastname: Ledbetter
mesh_terms: D015703:Antigens, CD / Q000032:analysis / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000502:physiology; D000954:Antigens, Surface / Q000502:physiology*; D018122:B7-1 Antigen; D018821:CD18 Antigens; D018106:CD28 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002478:Cells, Cultured; D019040:E-Selectin; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D008213:Lymphocyte Activation; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D018122:B7-1 Antigen; D018821:CD18 Antigens; D018106:CD28 Antigens; D015815:Cell Adhesion Molecules; D019040:E-Selectin; C065289:ICAM2 protein, human; D018799:Intercellular Adhesion Molecule-1