title: Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis.
abstract: Lewis rats are susceptible to several forms of experimental arthritis-induced using heat-killed Mycobacterium tuberculosis (adjuvant arthritis, or AA), streptococcal cell walls, collagen type II, and the lipoidal amine CP20961. Prior immunization with the mycobacterial 65-kD heat shock protein (hsp65) was reported to protect against AA, and other athritis models not using M. tuberculosis, via a T cell-mediated mechanism. Hsp65 shares 48% amino acid identity with mammalian hsp60, which is expressed at elevated levels in inflamed synovia. Several studies have reported cross-reactive T cell recognition of mycobacterial hsp65 and self hsp60 in arthritic and normal individuals. We previously described nine major histocompatibility complex class II-restricted epitopes in mycobacterial hsp65 recognized by Lewis rat T cells. Of these only one, covering the 256-270 sequence, primed for cross-reactive T cell responses to the corresponding region of rat hsp60. Here we have tested each hsp65 epitope for protective activity by immunizing rats with synthetic peptides. A peptide containing the 256-270 epitope, which induced cross-reactive T cells, was the only one able to confer protection against AA. Similarly, administration of a T cell line specific for this epitope protected against AA. Preimmunization with the 256-270 epitope induced T cells that responded to heat-shocked syngeneic antigen-presenting cells, and also protected against CP20961-induced arthritis, indicating that activation of T cells, recognizing an epitope in self hsp60 can protect against arthritis induced without mycobacteria. Therefore, in contrast to the accepted concept that cross-reactive T cell recognition of foreign and self antigens might induce aggressive autoimmune disease, we propose that cross-reactivity between bacterial and self hsp60 might also be used to maintain a protective self-reactive T cell population. This discovery might have important implications for understanding T cell-mediated regulation of inflammation.
authors.affiliation: Institute of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, The Netherlands.
authors.forename: S M
authors.initials: SM
authors.lastname: Anderton
authors.forename: R
authors.initials: R
authors.lastname: van der Zee
authors.forename: B
authors.initials: B
authors.lastname: Prakken
authors.forename: A
authors.initials: A
authors.lastname: Noordzij
authors.forename: W
authors.initials: W
authors.lastname: van Eden
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000517:prevention & control*; D001426:Bacterial Proteins; D002460:Cell Line; D018834:Chaperonin 60 / Q000276:immunology*; D018833:Chaperonins / Q000276:immunology; D003429:Cross Reactions; D006360:Heat-Shock Proteins / Q000276:immunology; D007114:Immunization; D008213:Lymphocyte Activation; D008297:Male; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001426:Bacterial Proteins; D018834:Chaperonin 60; D006360:Heat-Shock Proteins; D010446:Peptide Fragments; C074119:heat-shock protein 65, Mycobacterium; D018833:Chaperonins