Biased dependency of CD80 versus CD86 in the induction of transcription factors regulating the human IL-2 promoter.

Abstract

In addition to the signals obtained by ligation of the TCR, T cells need additional, co-stimulatory signals to be activated. One such co-stimulatory signal is delivered when CD28 on T cells binds to CD80 or CD86 on antigen-presenting cells (APC). In the present study, we analyzed the ability of CD80 and CD86 to co-stimulate human T cells activated by superantigen. Using the Raji B cell lymphoma, which express similar levels of CD80 and CD86, it was found that T cell proliferation was mainly co-stimulated by CD80. To further characterize the consequences of this biased co-stimulatory dependency, we employed a well-defined system of transfected CHO cells expressing human MHC class II together with CD80, CD86 or CD80 and CD86. Proliferation of freshly prepared CD4+ T cells required the presence of either CD80 or CD86. However, IL-2 production reached only suboptimal levels in the presence of CD86 but optimal levels with CD80. To analyze IL-2 transcriptional activity in CD80 and CD86 co-stimulated T cells we used Jurkat T cells transfected with luciferase reporter gene constructs. CD80 induced higher levels of IL-2 promoter-enhancer activity compared to CD86. Furthermore, the activity of transcription factors regulating the IL-2 promoter-enhancer region including activation protein-1, CD28 response element and nuclear factor kappaB were 4-8 times higher after CD80 compared to CD86 ligation. Our results suggest that the eventual appearance of CD80 on recently activated CD86+ APC is important for the superinduction of IL-2 production and to support vigorous T cell proliferation.