Abstract

Activation of T lymphocytes requires at least two distinct signals for full cellular response. Signal oneinvolves the engagement of the T cell receptor (TCR) by antigen specific peptide-MHC complexes.The signal two is provided by the interaction of costimulatory molecules on the antigen presentingcells (APC) and the corresponding counter receptors on the T cells. In this way, to mimic the two-signal requirements for T cell activation mediated by ligands, we exposed the superantigens SEA orSEE (signal 1) to T cells incubated with HLA-DR/LFA-3 or HLA-DR/B7-1-CHO transfected cells(signal 2). LFA-3 costimulation was able to induce T cell proliferation as well as IFN-γ and IL-4production at similar levels as in cells induced by B7-1. Analysis of the CD28RE of the IL-2 promotershowed specific transcription factor recruitment at the CD28RE element upon induction by B7 1/SEE.Further functional studies with an IL-2 enhancer-promoter carrying either wild type or mutatedversions of the CD28RE site revealed that this element is necessary for full activation upon B7-1costimulation. While both CD28/B7-1 and CD2/LFA-3 costimulation resulted in the up-regulation of IL-4 and IFN-γ promoters, IL-2 promoter activity and production of IL-2 were only seen after B7-1costimulation. However, contrary to what has been previously proposed, we show that costimulationwith either B7-1 or LFA-3 further enhanced the ERK-2 activity and strongly activated the p38 MAPKpathway, but only B7-1 costimulation induced high levels of JNK-1 activity. These data suggest thatthe differential effect of CD28 vs. CD2 can be related to the difference in the ability of the twopathways to induce JNK-1 activity.