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OBJECTIVE: In autoimmune situations, the outcome of immune response against a disease-related antigen is typically viewed in terms of the balance between the pathogenic versus the protective subsets of antigen-reactive T cells. Using the rat adjuvant arthritis (AA) model of human rheumatoid arthritis (RA), we examined the antigen specificity and the functional attributes of the T cell repertoire directed against defined pathogenic versus protective epitopes of heat-shock protein 65 (hsp65), and determined the immunologic basis of the AA-protective effect of subsets of T cells primed by the pathogenic determinant. METHODS: Lewis (RT.1l) rats were pretreated subcutaneously with the pathogenic epitope 177-191 of mycobacterial hsp65 (B177) in adjuvant (incomplete Freund's adjuvant/complete Freund's adjuvant/CpG) and then immunized with heat-killed M. tuberculosis H37Ra for disease induction. The antigen specificity/crossreactivity of the T cells primed by B177 or the AA-protective determinant 465-479 of the homologous rat hsp65 (R465) was tested by using proliferation assay, cytokine ELISA, tolerance induction, and adoptive transfer. RESULTS: Pretreatment of Lewis rats with the arthritogenic determinant B177 using an immunogenic rather than a tolerogenic regimen affords protection against AA instead of initiation or aggravation of AA. This protective effect of B177 is mediated in part by activation of T cells that are crossreactive with R465. CONCLUSION: Downmodulation of AA by a pathogenic foreign epitope involving T cells crossreactive with a distant, protective self-determinant represents a novel aspect of immune regulation, and suggests further exploration of the use of pathogenic epitopes for the treatment of autoimmune arthritis.