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

Abstract

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 (TH1) 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. 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.