Differential effects of CD28 engagement and IL-12 on T cell activation by altered peptide ligands

To further our understanding of the mechanisms underlying the diverse effec ts of altered peptide Ligands (APL) on T cell activation, we used a populat ion of nonactivated spleen cells from mice that expressed a transgenic TCR specific for myelin basic protein Acl-ll and peptide analogues that display either enhanced or decreased affinities for TCR/MHC to address the questio n whether APL-induced signaling through the TCR can regulate the capability of APC to activate T cells, We demonstrate that weak agonists APL are poor inducers of all aspects of the activation of both the responder T cells an d the APC, Enhancement of the antigenic signal by augmenting the binding of the weak agonists to MHC reversed their defective activating capacity, Enh ancement of costimulation by engagement of CD28 only resulted in augmentati on of the capacity of the weak agonist APL to induce proliferation and IL-2 /IL-3 production, but not CD40L or IL-12R beta 2 chain expression on T cell s, CD80/CD86 expression on APC, IL-12 secretion, or IFN-gamma production, E xogenous IL-12 promoted IFN-gamma production in the presence of the weak ag onists, These studies demonstrate that there is a critical threshold of ant igenic signal required for full activation of the T cell-APC interactions n eeded for the differentiation of Th1 cells. The provision of excess costimu lation can overcome some of the defects in T cell activation by weak agonis ts, but is insufficient to induce a sufficient level of CD40L expression ne eded for engagement of CD40 on APC with subsequent IL-12 production and ind uction of IL-12R beta 2 chain expression.