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J. Biol. Chem., Vol. 281, Issue 43, 32676-32683, October 27, 2006

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Isoaspartyl Post-translational Modification Triggers Anti-tumor T and B Lymphocyte Immunity^*

Hester A. Doyle¹, Jing Zhou¹, Martin J. Wolff, Bohdan P. Harvey, Robert M. Roman, Renelle J. Gee, Raymond A. Koski, and Mark J. Mamula²

From the Yale University School of Medicine, New Haven, Connecticut 06520 and L2 Diagnostics, New Haven, Connecticut 06511

A hallmark of the immune system is the ability to ignore self-antigens. In attempts to bypass normal immune tolerance, a post-translational protein modification was introduced into self-antigens to break T and B cell tolerance. We demonstrate that immune tolerance is bypassed by immunization with a post-translationally modified melanoma antigen. In particular, the conversion of an aspartic acid to an isoaspartic acid within the melanoma antigen tyrosinase-related protein (TRP)-2 peptide-(181-188) makes the otherwise immunologically ignored TRP-2 antigen immunogenic. Tetramer analysis of iso-Asp TRP-2 peptide-immunized mice demonstrated that CD8⁺ T cells not only recognized the isoaspartyl TRP-2 peptide but also the native TRP-2 peptide. These CD8⁺ T cells functioned as cytotoxic T lymphocytes, as they effectively lysed TRP-2 peptide-pulsed targets both in vitro and in vivo. Potentially, post-translational protein modification can be utilized to trigger strong immune responses to either tumor proteins or potentially weakly immunogenic pathogens.

Received for publication, May 19, 2006 , and in revised form, August 10, 2006.

^* This work was supported by National Institutes of Health Grants CA-101542 and AI-48120 (to M. J. M.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Yale University School of Medicine, P. O. Box 208031, New Haven, CT 06520-8031. Tel.: 203-737-2480; Fax: 203-785-7053; E-mail: mark.mamula{at}yale.edu.

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