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.

Tumour cell expression of B7 costimulatory molecules and interleukin-12 or granulocyte–macrophage colony-stimulating factor induces a local antitumour response and may generate systemic protective immunity

“…47 In a number of in vivo and in vitro studies, B7-1 and B7-2 were found to favour secretion of different profiles of cytokines, [48][49][50] though other studies have not found any differences. [51][52][53] Expression of B7-2 in CMT93 colorectal tumour cells resulted in a decrease in their tumourigenicity, similar to the effects of B7-1 expression we had described previously. 20 However, unlike B7-1, the B7-2-expressing cells induced a significant degree of protective immunity relative to that elicited by the parental tumour.…”

Lentivirus-mediated gene transfer in primary T cells is enhanced by a central DNA flap

“…In this context, it is notable that the CD8 + cells were transduced 4-6 days following T cell receptor (TCR) activation, a period during which there is a significant secretion of cytokines. 41,42 In contrast, in our lentiviral transduction experiments which were performed at an earlier time-point, 24 h post-TCR activation, and in those reported by Costello and colleagues, 43 performed 48 h after activation, gene transfer efficiencies in CD4 + and CD8 + T cells were equivalent. Moreover, Uckert et al 31 found that CD8 + T cells were transduced very inefficiently with a GALV-pseudotyped MuLV vector following a relatively long prestimulation (4-6 days), while we detected high MuLV-mediated transduction of CD8 + T cells following a 24-h stimulation.…”

CD40/CD40 Homodimers Are Required for CD40-induced Phosphatidylinositol 3-Kinase-dependent Expression of B7.2 by Human B Lymphocytes

“…Although B7.2 is known to be regulated by CD40 ligation on B cells (34), our results demonstrated for the first time that CD40-mediated B7.2 expression depends on PI 3-kinase activation. Thus, CD40 dimer formation by CD154 in vivo could provide an additional mechanism for regulating CD28/B7.2 interactions that are essential for initiating antigen-specific T cell responses, up-regulating cytokine expression, and promoting T cell expansion and differentiation (42)(43)(44)(45).…”