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EAE Tolerance Induction with Hsp70-Peptide Complexes Depends on H60 and NKG2D Activity¹

Grazyna Galazka^2,*, Anna Jurewicz^2,*, Wojciech Orlowski^*, Mariusz Stasiolek^*, Celia F. Brosnan, Cedric S. Raine and Krzysztof Selmaj^3,*,

^* Department of Neurology, Medical University of Lodz, Lodz, Poland; and Department of Pathology (Neuropathology), Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461

Inflammation leads to induction of tissue stress conditions that might contribute to the generation of mechanisms limiting ongoing immune responses. We have shown previously that peptides derived from brain tissue of mice with experimental autoimmune encephalomyelitis (EAE) complexed with the chaperone heat shock protein 70 (Hsp70-pc) induce an NK-cell-dependent tolerance for subsequent EAE sensitization. We now present data that showed that the MHC class I-related glycoprotein H60 determines Hsp70-pc-induced EAE inhibition. Hsp70-pc led to significant and selective up-regulation of H60 expression in SJL/J mice, and Ab-blocking of H60 expression led to loss of EAE tolerance. Similarly, blocking of the NK cell receptor for H60, NKG2D, also reversed the Hsp70-pc-induced EAE inhibition. In contrast, in C57BL/6 mice H60 was not expressed, and Hsp70-pc-induced tolerance was not detected. The NK cell mediated Hsp70-pc-induced tolerance to EAE was dependent on modulation of dendritic cells function leading to diminished T cell reactivity to PLP. As, no increase of H60 expression on T cells from EAE mice immunized with PLP was detected, and no enhanced loss of CD3⁺H60⁺over CD3⁺H60^– cells in Hsp70-pc-induced EAE tolerance was found direct killing of H60⁺ PLP-reactive cells seems not to be involved in the Hsp70-pc-induced tolerance induction. We have provided evidence that Hsp70-pc-induced tolerance for EAE, mediated by NK cells, involves induction of H60 ligand and its interaction with NKG2D receptor. NK cells tolerization of EAE depends on altered dendritic cells activity leading to enhanced death of Ag reactive cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the KBN Grant 6 PO4A 05618, PBZ-MIN-005/P04/2002/10, U.S. Public Health Service Grants NS11920 and NS31919, and NMSS RG 1001-K-11.

² G.G. and A.J. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Krzysztof Selmaj, Department of Neurology, Medical University of Lodz., 22, Kopcinskiego Street, Lodz, Poland. E-mail address: kselmaj{at}afazja.am.lodz.pl

⁴ Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; Hsp, heat shock protein; 7-AAD, 7-aminoactinomycin; DC, dendritic cell; SA-PE, streptavidin-PE; CFDA-SE, 5-(and-6)-carboxyfluorescein diacetate-CFSE; SC, spleen cells; PPD, purified protein derivative.

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