Murine B7 antigen provides an efficient costimulatory signal for activation of murine T lymphocytes via the T-cell receptor/CD3 complex.

Abstract

We demonstrate that the murine B7 (mB7) protein is a potent costimulatory molecule for the activation of resting murine CD4+ T cells through the T-cell receptor (TCR)/CD3 complex. Stable mB7-transfected Chinese hamster ovary cells, but not vector-transfected controls, synergize with anti-CD3 monoclonal antibody and Con A-induced T-cell activation, resulting ultimately in proliferation. mB7 exerted its effect by inducing production of interleukin 2 and expression of the interleukin 2 receptor. Thus, mB7 costimulates T-cell activation through the TCR/CD3 complex by positively modulating the normal pathway of T-cell expansion. In contrast to the pronounced effect of mB7 on the activation of T cells through the TCR/CD3 complex, the mB7-transfected CHO cell line costimulated T-cell activation via the glycosylphosphatidylinositol-anchored proteins Thy-1 and Ly-6A.2 only inefficiently. Finally, the combination of a calcium ionophore and mB7 is not sufficient to cause T-cell proliferation, while the combination of a calcium ionophore and phorbol 12-myristate 13-acetate (PMA) stimulates T cells efficiently. The signals that mB7 and PMA provide for murine T lymphocyte activation are therefore not interchangeable, although both costimulate activation through the TCR/CD3 complex.Stimulation of highly purified CD4+ T lymphocytes with peptide-major histocompatibility complex (MHC) complexes, monoclonal antibodies (mAbs) against T-cell receptor (TCR)/CD3 complexes, lectins, or mAbs against the glycosyl-phosphatidylinositol (GPI)-anchored proteins Thy-1 and Ly-6A.2 does not lead to cell proliferation or lymphokine secretion. The above activation pathways require a second, costimulatory, signal for lymphokine gene expression and proliferation that is provided by an antigen-presenting cell (APC) or by pharmacological reagents such as phorbol 12-myristate 13-acetate (PMA) (1, 2).The nature of the costimulatory signal appears to be dependent upon the subset of CD4+ T cells that is activated. On the basis of their capacity to secrete specific lymphokines, two types of murine CD4+ T-helper cells were defined originally. Th-1 clones synthesize interleukin (IL)-2, interferon y, and lymphotoxin, whereas Th-2 clones secrete IL-4, IL-5, and IL-6 (3). In the case of Th-2 type CD4+ T cells, this costimulatory signal appears to be IL-1 (4). In contrast, the nature of the costimulatory signal for Th-1-type CD4+ T cells is unknown. Recent data in the human system suggest that B7, a 45-to 60-kDa cell surface glycoprotein present on activated B cells and on interferon-y-stimulated monocytes/macrophages (5, 6), may be costimulatory for Th-1 CD4+ T cells. Transfected cell lines that express human B7 or recombinant B7-immunoglobulin fusion protein can synergize with anti-CD3 or phytohemagglutinin-driven T-cell activation (7-9). Furthermore, binding of mAbs to CD28, a 44-kDa homodimeric T-cell glycoprotein that is a receptor for B7 (10), can augment the proliferation or lymphokine secretion of T cells stimulated with suboptimal doses of anti...

Thy-1 Signaling in the Context of Costimulation Provided by Dendritic Cells Provides Signal 1 for T Cell Proliferation and Cytotoxic Effector Molecule Expression, but Fails to Trigger Delivery of the Lethal Hit

“…Thy-1-driven T cell proliferation similarly depended on both B7-1-and B7-2-mediated costimulation. Our results are in stark contrast with an earlier report that relatively inefficient CD4 ϩ T cell proliferation and IL-2 synthesis occur in response to the G7 anti-Thy-1 mAb in a xenogeneic system that used B7-transfected Chinese hamster ovary cells as accessory cells (42). However, because B7-2 was not identified at the time, the failure of B7-1-transfected Chinese hamster ovary cells to optimally costimulate Thy-1-driven responses could be at least in part due to a lack of CD28-B7-2 interactions.…”

T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo.

“…In vitro studies have demonstrated that CD28 is the surface receptor of a cyclosporin A-resistant T-cell signal transduction pathway (10). Stimulation of CD28 by its natural ligand B7 provides costimulation to TCR-activated T cells, leading to proliferation and lymphokine gene expression (4,(11)(12)(13)(14).…”

Costimulator deficient antigen presentation by an endothelial cell line induces a nonproliferative T cell activation response without anergy.

“…The best-defined costimulatory system in T ceil activation is that involving B7-CD28 interactions (23,(49)(50)(51)(52)(53)(54)(55). There are two reasons why it is unlikely that the absence or presence of B7 is playing a significant role in the T cell functional responses described here.…”