Biased dependency of CD80 versus CD86 in the induction of transcription factors regulating the human IL-2 promoter.
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.
Olsson
C
C
Pharmacia & Upjohn, Lund Research Center, Sweden.
Michaëlsson
E
E
Parra
E
E
Pettersson
U
U
Lando
P A
PA
Dohlsten
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D018122:B7-1 Antigen / Q000276:immunology / Q000502:physiology*; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016466:CHO Cells / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis / Q000502:physiology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000502:physiology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018089:Superantigens / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000502:physiology; D014158:Transcription, Genetic
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D018089:Superantigens; D018808:Transcription Factor AP-1; D014157:Transcription Factors