Since the initial discovery of the protective role of heat shock protein (HSP) 60 in arthritis, T cell recognition of endogenous HSP was found to be one of the possible underlying mechanisms. Recently we have uncovered potent disease-suppressive Tregs (anti-inflammatory immunosuppressive T cells) recognizing HSP70 self-antigens, and enabling selective targeting of such Tregs to inflamed tissues. HSP70 is a major contributor to the major histocompatibility complex (MHC) Class II ligandome and we have shown that a conserved HSP70-epitope (B29) is abundantly present in murine MHC Class II. Upon transfer, B29-induced CD4+CD25+Foxp3+T cells suppressed established proteoglycan-induced arthritis (PGIA) in mice. These self-antigen specific Tregs were activated in vivo and as little as 4.000 cells sufficed to fully inhibit arthritis. Furthermore, in vivo depletion of transferred Tregs abrogated disease suppression. Given that B29 can be presented by most human MHC class II molecules and that B29 inhibited arthritis in HLA-DQ8 (human MHC) transgenic mice, we feel that therapeutic vaccination with selected HSP peptides can be an effective route for induction of anti-inflammatory Tregs as a novel intervention in chronic inflammatory diseases.