T lymphocyte activation necessitates at least two unique signals for a complete cellular response. The first signal involves antigen-specific peptide-MHC complexes binding to the T cell receptor (TCR). The interaction of costimulatory molecules on antigen presenting cells (APC) with the corresponding counter receptors on T cells provides signal two. To simulate the two-signal requirement for ligand-mediated T cell activation, we exposed T cells to the superantigens SEA or SEE (signal 1) incubated with HLA-DR/LFA-3 or HLA-DR/B7-1-CHO transfected cells (signal 2). T cell proliferation, as well as IFN- and IL-4 production, were induced by LFA-3 costimulation at similar levels to those induced by B7-1. When B7 1/SEE was induced, particular transcription factors were recruited to the CD28RE region of the IL-2 promoter, according to analysis. Further functional investigations using an IL-2 enhancer-promoter containing either wild type or mutant CD28RE sites indicated that this element is required for complete activation under B7-1 costimulation. While both CD28/B7-1 and CD2/LFA-3 costimulation resulted in up-regulation of IL-4 and IFN- promoters, only B7-1 costimulation resulted in IL-2 promoter activity and IL-2 production. However, we show that costimulation with either B7-1 or LFA-3 increased ERK-2 activity and substantially activated the p38 MAPK pathway, but only B7-1 costimulation caused high levels of JNK-1 activity, contrary to earlier speculation. These findings show that the difference in CD28 vs. CD2 impact is due to a difference in the two routes' ability to generate JNK-1 activity.
Author(S) Details
Eduardo Parra
Laboratory of Experimental Biomedicine, School of Medicine, FACSAL, University of Tarapacá, Avenida Senador Luis Valente Rossi, Arica, Chile.
Pedro Hecht
Laboratory of Experimental Biomedicine, School of Medicine, FACSAL, University of Tarapacá, Avenida Senador Luis Valente Rossi, Arica, Chile.
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