THE DIVESITY IN ANTIGEN RECOGNITION AND RESPONSE OF ANTIGEN-SPECIFIC HUMAN CD4^+ T-CELL CLONES

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Autoimmune diseases are developed when a specific adaptive immune response is directed against self antigens, to which the immune system is supposed to be tolerated in healthy condition. One of the hypothesized mechanisms that break the tolerance is explained by a molecular mimicry model, where self-reactive T cells were primed by infectious microorganisms carrying T-cell epitopes closely-related to the self-antigenic peptides. Indeed, evidence is accumulating that the degeneracy in epitopes recognized by a T cell clone is higher than that expected before. In the present study, we analyzed the signal transduction pathways of the T cells stimulated with slightly modified antigenic peptides (altered peptide ligands ; APLs), characterized the diversity of the T-cell epitopes recognized by self-reactive T-cell clones associated with an autoimmune disease, and identified microorganism-derived non-self antigenic peptides that were recognized by the T-cell clones. We obtained the following re … More sults :1) Some partially agonistic APLs derived from a non-self streptococcal peptide could stimulate the cognate human CD4^+ T-cell (Th cell) clone to proliferate when they were over-expressed on the surface of antigen presenting cells. However, the proliferative T-cell responses were unique in that they were not accompanied with detectable T-cell receptor (TCR)-proximal signaling events such as phosphorylation of ZAP-70 and LAT and down-regulation of the TCR, all of which were apparently observed in the T cells stimulated with the original antigenic peptide.2) We established a T-cell epitope-expression library using CLIP-substituted invariant chain and identified diverse T-cell epitopes that were recognized by Th-cell clones. Using the modified libraries in which randomized amino acid residues were narrowed down into three successive ones, we characterized the degeneracy in the epitopes of the GAD65-reactive Th-cell clones derived from IDDM patients and identified the Streptcoccus pneumoniae- and Staphylococcus aureus-derived epitopes to which the Th-cell clones cross-reacted. Less