title: Costimulation via vascular cell adhesion molecule-1 induces in T cells increased responsiveness to the CD28 counter-receptor B7.
abstract: Optimal stimulation of CD4+ T cells in an immune response requires not only signals transduced via the CD3/TCR complex but also costimulatory signals delivered as a consequence of interactions between T-cell surface-associated costimulatory R and their counter-R on APC. CD28 plays a crucial role as a dominant costimulatory R during the induction of CD4+ T-cell proliferation by interacting with counter-R B7 on APC to sustain IL-2 production. The absence of CD28-mediated costimulation has been postulated to result in T-cell anergy or unresponsiveness. The costimulatory effects of CD28 can be generated with its natural counter-R B7 or mAb directed at CD28. Using soluble C gamma 1 chimeras of B7, ICAM-1, and VCAM-1, we have recently shown that B7 costimulates TCR-dependent proliferation of Ag-primed CD4+ T cells more efficiently than that of resting nonactivated CD4+ T cells. In contrast, proliferation of resting CD4+ T cells can be efficiently costimulated by either ICAM-1 or VCAM-1 via interactions with their R CD11a/CD18 (LFA-1/beta 2 integrin) and CD29/CD49d (VLA-4/beta 1 integrin), respectively. TCR-directed preactivation of resting CD4+ T cells with ICAM-1 can induce increased responsiveness to B7 costimulation. In this study, we show that prior TCR-directed activation of resting CD4+ T cells with VCAM-1 induced increased responsiveness to B7 costimulation. VCAM-1 also synergized with B7 to bring about supraoptimal proliferation of CD4+ T cells. In addition, costimulation of resting T cells with VCAM-1 significantly increased not only surface expression of CD28 but also CD28-mediated mobilization of intracellular free [Ca2+]i. Similar activation of T cells with fibronectin also resulted in increased B7 responsiveness, suggesting the involvement of VLA-4 molecule. VCAM-1 costimulation induced hyperresponsiveness to B7 costimulation in both CD18+ (normal) and CD18- (leukocyte adhesion deficient) T cells. Thus, VCAM-1 may play an important costimulatory role during the activation of resting T cells and, by augmenting responsiveness to B7, facilitate optimal development of immunological memory in addition to various regulatory and effector functions.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
authors.forename: N K
authors.initials: NK
authors.lastname: Damle
authors.forename: K
authors.initials: K
authors.lastname: Klussman
authors.forename: G
authors.initials: G
authors.lastname: Leytze
authors.forename: H D
authors.initials: HD
authors.lastname: Ochs
authors.forename: A
authors.initials: A
authors.lastname: Aruffo
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: J A
authors.initials: JA
authors.lastname: Ledbetter
mesh_terms: D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology*; D018122:B7-1 Antigen; D018106:CD28 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000097:blood; D015815:Cell Adhesion Molecules / Q000502:physiology*; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D011971:Receptors, Immunologic / Q000276:immunology*; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D018122:B7-1 Antigen; D018106:CD28 Antigens; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D011971:Receptors, Immunologic; D019010:Vascular Cell Adhesion Molecule-1; D002118:Calcium