T-cell signaling in response to altered myelin basic protein peptides

Experimental autoimmune encephalomyelitis (EAE) can be induced in H-2k mice with the N-terminal peptide of myelin basic protein (MBP). Helper T-cells type 1 (T_H1) specific to the MBP Ac(1-11) peptide mediate the autoimmune response and it has been previously shown that the progression of EAE can be inhibited by altered peptide ligands (APLs) that apparently target these T cells. However, there have not been any strong correlations between the in vitro reactivity of a given APL and its efficacy in blocking disease. We hypothesized that if a large number of APLs are evaluated, they will segregate into subsets defined by their activity as measured by different assays for in vitro T-cell activation. We suggest that those peptides with therapeutic efficacy will be primarily contained within one subset. Computer models were used to design altered MBP Ac(1-11) peptides that incorporated both natural and non-natural amino acids. The peptides were screened with various cell-based assays against a panel of monoclonal MBP Ac(1-11)-specific T-cell clones derived from B10.A mice that had been primed with MBP protein. A number of peptides with antagonist or partial agonist activities were identified. A hierarchy of activities was defined based on the ability of a peptide to induce early signaling, proliferation, cytokine production, and antagonism. In addition, a more extensive study of responses by one of the T-cell clones showed a hierarchy of T-cell effector functions. Among the peptides identified as antagonists, the most potent also demonstrated partial agonist activities.{09}The in vitro reactivity of the altered peptides within this group is similar to the activities of peptides previously shown to be effective in blocking EAE.