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T-cell recognition of MHC-peptide complexes shows a high degree of polyspecificity extending to recognition of a large number of structurally unrelated peptides. Examples of polyspecificity reported to date are confined to recognition of epitopes from distinct proteins or synthetic peptide libraries. Here we describe intramolecular polyspecificity of CD4 T cells specific for several epitopes within proteoglycan aggrecan, a structural glycoprotein of cartilage and candidate autoantigen in rheumatoid arthritis. T-cell hybridomas from aggrecan-immunized mice recognized four structurally unrelated epitopes from the G1 domain of aggrecan, but not other aggrecan epitopes or a variety of other peptide epitopes restricted by the same MHC class II allele. We also showed that the hierarchy of cross-reactivity broadly correlated with the strength of peptide binding to MHC class II. Similar polyspecificity was observed in responses of lymph node cells from peptide-immunized mice, suggesting polyspecificity of a significant proportion of the in vivo aggrecan specific T-cell repertoire. Polyspecific recognition of several epitopes within the same autoantigen may provide a novel mechanism to reach the activation threshold of low-affinity autoreactive T cells in the initiation of autoimmune diseases. [ABSTRACT FROM AUTHOR]