CD28 ligands CD80 (B7-1) and CD86 (B7-2) induce long-term autocrine growth of CD4+ T cells and induce similar patterns of cytokine secretion in vitro

Abstract

The interaction of CD28 and its ligands is critical for antigen-induced T cell activation. Recent studies have demonstrated the existence of at least two members of the B7 receptor family. In this report, the co-stimulatory signals provided by CD80 (B7-1) or CD86 (B7-2) were compared to CD28 ligation by mAb. We demonstrate that the kinetics of induction of T cell proliferation after anti-CD3 stimulation was similar regardless of the form of co-stimulation. Similarly, B7-1 and B7-2 could both maintain long-term expansion of CD4 cells. The co-stimulatory effects of both B7-1 and B7-2 were dependent on CD28 cross-linking, based on complete inhibition of proliferation by CD28 antibody Fab fragments. Co-stimulation with B7-1 and B7-2 induced high levels of cytokine secretion by resting T cells, and the effects of B7-1 and B7-2 could not be distinguished. This conclusion is based on analysis of the initial activation of CD28+ T cells, as well as T cell subpopulations consisting of CD4+ and CD8+ T cells. Both B7-1 and B7-2 could elicit IL-4 secretion from CD4+ T cells while anti-CD28 antibody induced substantially less IL-4 secretion. Furthermore, both B7-1 and B7-2 could stimulate high levels of IFN-gamma and IL-4 from CD4+CD45RO+ cells, while neither B7 receptor could co-stimulate IFN-gamma and IL-4 secretion from CD4+CD45RA+ T cells. B7-1 and B7-2 could, however, co-stimulate CD4+CD45RA+ T cells to secrete IL-2. By contrast, when previously activated T cells were tested, re-stimulation of CD4+ T cell blasts with B7-1 or B7-2 resulted in higher secretion of IL-4 and IL-5 than anti-CD28, while re-stimulation with anti-CD28 antibody maintained a higher level of secretion of IL-2 and IFN-gamma than B7-1 or B7-2. These observations may have important implications because they suggest that the manner of CD28 ligation can be a critical determinant in the development of cytokine secretion that corresponds to Th1- and Th2-like patterns of differentiation. Together these observations suggest that there are no intrinsic differences between B7-1 and B7-2 in their ability to co-stimulate the populations of cells that we have tested.