B7-Dc, a New Dendritic Cell Molecule with Potent Costimulatory Properties for T Cells

Functional interactions between T and B lymphocytes are necessary for optimal activation of an immune response. Recently, the T lymphocyte receptor CD28 was shown to bind the B7 counter-receptor on activated B lymphocytes, and subsequently to costimulate interleukin 2 production and T cell proliferation. CTLA-4 is a predicted membrane receptor from cytotoxic T cells that is homologous to CD28 and whose gene maps to the same chromosomal band as the gene for CD28. It is not known, however, if CD28 and CTLA-4 also share functional properties. To investigate functional properties of CTLA-4, we have produced a soluble genetic fusion between the extracellular domain of CTLA-4 and an immunoglobulin C gamma chain. Here, we show that the fusion protein encoded by this construct, CTLA4Ig, bound specifically to B7-transfected Chinese hamster ovary cells and to lymphoblastoid cells. CTLA4Ig also immunoprecipitated B7 from cell surface 125I-labeled extracts of these cells. The avidity of 125I-labeled B7Ig fusion protein for immobilized CTLA4Ig was estimated (Kd approximately 12 nM). Finally, we show that CTLA4Ig was a potent inhibitor of in vitro immune responses dependent upon cellular interactions between T and B lymphocytes. These findings provide direct evidence that, like its structural homologue CD28, CTLA- 4 is able to bind the B7 counter-receptor on activated B cells. Lymphocyte interactions involving the B7 counter-receptor are functionally important for alloantigen responses in vitro.

Immunostimulatory properties of dendritic cells (DCs) are linked to their maturation state. Injection of mature DCs rapidly enhances antigen-specific CD4+ and CD8+ T cell immunity in humans. Here we describe the immune response to a single injection of immature DCs pulsed with influenza matrix peptide (MP) and keyhole limpet hemocyanin (KLH) in two healthy subjects. In contrast to prior findings using mature DCs, injection of immature DCs in both subjects led to the specific inhibition of MP-specific CD8+ T cell effector function in freshly isolated T cells and the appearance of MP-specific interleukin 10–producing cells. When pre- and postimmunization T cells were boosted in culture, there were greater numbers of MP-specific major histocompatibility complex tetramer-binding cells after immunization, but these had reduced interferon γ production and lacked killer activity. These data demonstrate the feasibility of antigen-specific inhibition of effector T cell function in vivo in humans and urge caution with the use of immature DCs when trying to enhance tumor or microbial immunity.

Occupancy of the T-cell antigen receptor is insufficient to induce T-cell activation optimally; a second co-stimulatory signal is required. Exposure of T-cell clones to complexes of antigen with major histocompatibility complex molecules in the absence of the co-stimulatory signal induces a state of clonal anergy. This requirement for two stimuli for T-cell activation could have an important role in vivo in establishing peripheral tolerance to antigens not encountered in the thymus. The receptor on T cells required for the co-stimulatory stimulus involved in the prevention of anergy has not been identified. The human T-cell antigen CD28 provides a signal that can synergize with T-cell antigen receptor stimulation in activating T cells to proliferate and secrete lymphokines. Here we report that a monoclonal antibody against the murine homologue of CD28 (ref. 7; J.A.G. et al., manuscript in preparation) can provide a co-stimulatory signal to naive CD4+ T cells and to T-cell clones. Moreover, we demonstrate that this co-stimulatory signal can block the induction of anergy in T-cell clones.