Distinct effects of CD86-mediated costimulation on resting versus activated human CD4+ T cells

CD80 and CD86 are important in the initiation of T cell immunity. Although their costimulatory function has long been appreciated, it remains unclear whether the biological significance of the two B7 isoforms resides in their different patterns and kinetics of expression or whether differences exist in their function. We have addressed this issue using HLA-DR1 transfectants co-expressing CD80, CD86, or both molecules as stimulators for naïve, memory, and activated human CD4+ T cells. Both CD80 and CD86 efficiently costimulated alloresponses by unseparated peripheral blood CD4+ T cells; however, CD86 was substantially inferior in costimulating alloresponses by separated memory T cells, and completely incompetent in costimulating three human T cell clones. Furthermore, CD80/CD86 double transfectants stimulated lower responses by the clones than cells expressing CD80 alone. That CD86 was actively inhibitory rather than merely neutral was evidenced by the increase in response to the double CD80/CD86 APC when anti-CD86 antibody was added. Furthermore, addition of anti-CTLA-4 Fab to cultures of HLA-DR1 transfectants co-expressing CD86, fully restored the proliferative response. These results indicate that CD80 and CD86 mediate distinct signals in previously activated T cells, and demonstrate that CTLA-4 ligation may dominate the outcome of CD86-mediated costimulation of activated CD4+ T cells.