AUTOLOGOUS RAT MYELIN BASIC-PROTEIN IS A PARTIAL AGONIST THAT IS CONVERTED INTO A FULL ANTAGONIST UPON BLOCKADE OF CD4 - EVIDENCE FOR THE INTEGRATION OF EFFICACIOUS AND NONEFFICACIOUS SIGNALS DURING T-CELL ANTIGEN RECOGNITION

A central question of TCR function is based on the observation that so me MHC ligands may bind TCR without stimulating biologic activity. To address the role of CD4 in this mechanism, we studied the interactions of the anti-CD4 mAb W3/25 with an encephalitogenic line of T helper c ells. Proliferative responses to guinea pig (GP) myelin basic protein (GPMBP) were mediated by distinct W3/25-sensitive and W3/25-insensitiv e mechanisms whereas responses to autologous rat (R) MBP (RMBP) were e xclusively mediated by W3/25-sensitive pathways. In assays of IL-2 pro duction, RMBP was a partial agonist that stimulated an intermediate le vel of IL-2 production but antagonized high levels of GPMBP-stimulated IL-2 production to that intermediate level. In the presence of W3/25, RMBP lacked stimulatory activity but instead exhibited inhibitory act ivity that completely blocked GPMBP-stimulated proliferative responses . The inhibitory mechanism did not involve antigenic competition for M HC glycoproteins, a blockade of mitogenic signaling, or induction of h igh zone tolerance. Rather, the mechanism involved specific occupancy of TCR with antagonistic MHC ligands derived from the 72-86 region of RMBP. In proliferative assays, GPMBP was similar to 10-fold more activ e than RMBP. In the presence of W3/25 however, GPMBP-induced agonism a nd RMBP-induced antagonism exhibited overlapping dose-response curves. RMBP and W3/25 not only fully inhibited GPMBP-stimulated proliferatio n, this synergistic combination also elicited an extended phase of T c ell anergy. In conclusion, RMBP-derived MHC ligands occupy TCR to exhi bit full efficacy for CD4-dependent signaling pathways while simultane ously lacking efficacy for W3/25-resistant signaling pathways. These d ata support an ''integrative'' model of T cell Ag recognition whereby MHC glycoproteins actively guide specific clustering of MHC-ligated TC R to enable quantitative comparisons of efficacious (nonself) and none fficacious (self) signals by T cells.