TCR AGONIST AND ANTAGONIST EXERT IN-VIVO CROSS-REGULATION WHEN PRESENTED ON IGS

Ig-PLP1 and Ig-PLP-LR are chimeric I,os expressing proteolipid protein (PLP)-derived T cell agonist (PLP1) and antagonist (PLP-LR) peptides, respectively. Both chimeras, like free PLP1 and PLP-LR peptides, indu ce in vivo-specific T cell responses. However, the responses induced b y Ig-PLP1 and Ig-PLP-LR were cross-reactive with both PLP1 and PLP-LR peptides, while those induced by free peptides were not. Surprisingly, despite the cross-reactivity of the responses, when Ig-PLP1 and Ig-PL P-LR were administered together into mice, a dose-dependent down-regul ation of both T cell responses and a reduction of IL-2 production to b ackground levels was observed. in contrast, when T cells induced by ei ther Ig chimera mere stimulated in vitro with mixtures of free PLP1 an d PLP-LR peptides, there was no down-regulation of proliferation or de crease in IL-2 production. These data indicate that Ig-PLP1 and Ig-PLP -LR exert adverse reactions on one another at the level of naive T cel ls, resulting in an opposite antagonism However, naive T cells experie ncing either chimera develop into cross-reactive cells, acquire resist ance to TCR triggering by closely related but different peptides, and support responsiveness.