Highly autoproliferative T cells specific for 60-kDa heat shock protein produce IL-4/IL-10 and IFN-gamma and are protective in adjuvant arthritis.
Previously we have shown that T cell responses to the mycobacterial 60-kDa heat shock protein (hsp60) peptide M256-270 mediated protection against adjuvant arthritis in Lewis rats. We have demonstrated now that M256-270-primed T cells become highly reactive to naive syngeneic APC upon repetitive restimulation in vitro with peptide M256-265, comprising the conserved core of peptide M256-270. These autoproliferative responses in the absence of added Ag were MHC class II restricted and resulted in the production of IL-4/IL-10 and IFN-gamma. Enhanced autoproliferation and expression of the cell surface molecule B7.2 by these T cells were observed in response to syngeneic heat-shocked APC, which indicated that the autoproliferation and expression of B7.2 resulted from the recognition of endogenously expressed and processed hsp. Despite their strong autoreactivity, upon transfer such T cells were found to induce a significant disease reduction in adjuvant arthritis. In contrast, T cells both primed and restimulated with peptide M256-270 became unresponsive toward syngeneic APC as well as toward the conserved core peptide M256-265, and they were devoid of protective capacity. This study demonstrates that the loss of self-tolerance toward hsp60 does not necessarily lead to autoimmune disease, but that hsp60-specific self-reactive and autoproliferative T cells may mediate T cell regulation in arthritis.
Paul
A G
AG
Faculty of Veterinary Medicine, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands.
van Kooten
P J
PJ
van Eden
W
W
van der Zee
R
R
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control*; D001324:Autoantigens / Q000276:immunology; D051940:B7-2 Antigen; D002460:Cell Line; D018834:Chaperonin 60 / Q000276:immunology* / Q000378:metabolism; D017124:Conserved Sequence; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000235:genetics / Q000276:immunology; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
D015703:Antigens, CD; D001324:Autoantigens; D051940:B7-2 Antigen; C497966:Cd86 protein, rat; D018834:Chaperonin 60; D018984:Epitopes, T-Lymphocyte; D006649:Histocompatibility Antigens; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; C038353:histocompatibility antigens RT, rat; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma