Differential requirement of CD28 for IL-12 receptor expression and function in CD4(+) and CD8(+) T cells.
IL-12 is a potent inducer of IFN-gamma production and Th1 responses. Co-stimulation mediated by B7 has been shown to synergize with IL-12 for optimal IFN-gamma production and proliferation in vitro. In this study, we examined the requirement of CD28/B7 interactions for optimal induction of IL-12 receptor(R) beta1 and beta2 expression and IFN-gamma. IL-12-induced IFN-gamma production and STAT4 nuclear translocation were markedly reduced in CD28(-/-) splenocytes compared to that of wild-type (WT) splenocytes. Analysis of IL-12R expression revealed that IL-12 induced similar levels of IL-12R beta2 mRNA expression in WT and CD28(-/-) cells. In contrast, IL-12R beta1 expression was impaired in CD28(-/-) cells, indicating that expression of IL-12R beta1 and beta2 is differentially regulated by CD28. CD28(-/-) CD4(+) but not CD8(+) cells exhibited a defect in IL-12Rbeta1 expression that was associated with a marked decrease in IL-12 binding as well as IL-12-induced IFN-gamma production. IL-2 could restore IL-12R expression to CD28(-/-) CD4(+) cells, however, this occurred independently of IL-2-induced proliferation. Thus, these findings identify distinct requirements for CD28 in the capacity of CD4(+) and CD8(+) cells to respond maximally to IL-12.
Elloso
M M
MM
University of Pennsylvania, School of Veterinary Medicine, Department of Pathobiology, Philadelphia 19104, USA.
Scott
P
P
D000818:Animals; D018106:CD28 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018123:Receptors, Interleukin / Q000502:physiology*; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000502:physiology
D018106:CD28 Antigens; D004268:DNA-Binding Proteins; C508440:Il12rb1 protein, mouse; C508443:Il12rb2 protein, mouse; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma