Differential function of CD80- and CD86-transfected human melanoma cells in the presence of IL-12 and IFN-gamma

Abstract

Introduction of co-stimulatory molecules like CD80 and CD86 represents a means to augment the immunogenicity of tumor cells and to induce immune responses directed at tumor antigens. Here we compared CD80- and CD86-transfected human melanoma cells to induce primary immune responses by their capacity to promote proliferation of human allogeneic resting T lymphocytes. CD80- and CD86-transfected SkMel63 melanoma cells induced T cell activation to a comparable degree, which was found to be independent of the cell surface density of these co-stimulatory molecules. Co-expression of CD80 and CD86 did not result in a synergistic increase in T cell proliferation. Both CD80 and CD86 transfectants induced the proliferation of isolated CD4+ or CD8+ T cells. Exogenous IL-2, IL-4 and tumor necrosis factor-alpha respectively enhanced primary T cell proliferation independent of CD80 or CD86 expression. Interestingly, differential activities of CD80 and CD86 were observed following stimulation of resting T cells in the presence of IL-12. Whereas IL-12 increased T cell proliferation in the presence of CD86-transfected melanoma cells, it exhibited an inhibitory function in the presence of CD80-expressing SkMel63 cells. Experimental evidence indicates that this inhibitory effect was mediated by IFN-gamma since (I) IFN-gamma secretion of stimulated T cells was augmented by IL-12, (II) exogenous IFN-gamma also inhibited T cell proliferation induced by CD80- but not CD86-transfected SkMel63 cells and (III) the inhibitory effect of IL-12 was blocked by an anti-IFN-gamma mAb.

Potential of CD80-transfected human breast carcinoma cells to induce peptide-specific T lymphocytes in an allogeneic human histocompatibility leukocyte antigens (HLA)-A2.1+-matched situation

“…However, it should be noted that we demonstrated recently that IL-12 only cooperates with CD86-mediated activation in rechallenge stimulations, but represses the proliferative response of naive cells. 29 Therefore, it is necessary to analyze the possible divergent effects of cytokines together with genetic tumor cell modifications prior to the assessment in clinical studies.…”

A cell surface-displayed anti-c-myc single-chain antibody: new perspectives for the genetic improvement of cellular tumor vaccines

“…However, as shown in Table 1, no large differences in the binding of the anti-CD28 scFv were observed between the anti-c-myc and the anti-CD3 SkMel63 transfectants. Because the human melanoma cell line SkMel63 used in these studies expresses little, if any, CD80 (B7.1) and CD86 (B7.2) ligands to the CD28 receptor, 10,15 these results probably reflect a low expression level of anti-c-myc scFv molecules on the tumor cell surface together with some unspecific binding and lack of binding of the anti-CD28 scFv to CD28 ligands.…”

Costimulatory Molecule Immune Enhancement in a Plasmid Vaccine Model Is Regulated in Part Through the Ig Constant-Like Domain of CD80/86

“…Although further investigation is required to refine these observations, the majority of reported studies agree that codelivery of plasmid CD86 and not CD80 in the DNA vaccine model induces a potent signal, which either initiates or expands in vivo cellular immune responses. Additionally, functional differences between CD80 and CD86 have been documented in many disease models (24,25,30,32,(33)(34)(35)(36)(37) including HIV infection (38 -42), where continuous CD28 signaling of HIV-1-infected cultured T cells resulted in viral clearance, whereas CTLA-4 signaling allowed for virus propagation (39 -41, 43). These results already suggest that there are differences between CD80 and CD86 leading to different functional interactions with CD28 and CTLA-4 receptors.…”