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Journal of Virology, January 2006, p. 883-890, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.883-890.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Three Immunoproteasome-Associated Subunits Cooperatively Generate a Cytotoxic T-Lymphocyte Epitope of Epstein-Barr Virus LMP2A by Overcoming Specific Structures Resistant to Epitope Liberation

Yoshinori Ito,1 Eisei Kondo,2 Ayako Demachi-Okamura,1 Yoshiki Akatsuka,1 Kunio Tsujimura,1 Mitsune Tanimoto,2 Yasuo Morishima,3 Toshitada Takahashi,1 and Kiyotaka Kuzushima1*

Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan,1 Department of Internal Medicine II, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan,2 Department of Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan3

Received 17 June 2005/ Accepted 19 October 2005

The precise roles of gamma interferon-inducible immunoproteasome-associated molecules in generation of cytotoxic T-lymphocyte (CTL) epitopes have yet to be fully elucidated. We describe here a unique epitope derived from the Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) presented by HLA-A*2402 molecules. Generation of the epitope, designated LMP2A222-230, from the full-length protein requires the immunoproteasome subunit low-molecular-weight protein 7 (ip-LMP7) and the proteasome activator 28-{alpha} subunit and is accelerated by ip-LMP2, as revealed by gene expression experiments using an LMP2A222-230-specific CTL clone as a responder in enzyme-linked immunospot assays. The unequivocal involvement of all three components was confirmed by RNA interference gene silencing. Interestingly, the LMP2A222-230 epitope could be efficiently generated from incomplete EBV-LMP2A fragments that were produced by puromycin treatment or gene-engineered shortened EBV-LMP2A lacking some of its hydrophobic domains. In addition, epitope generation was increased by a single amino acid substitution from leucine to alanine immediately flanking the C terminus, this being predicted by a web-accessible program to increase the cleavage strength. Taken together, the data indicate that the generation of LMP2A222-230 is influenced not only by extrinsic factors such as immunoproteasomes but also by intrinsic factors such as the length of the EBV-LMP2A protein and proteasomal cleavage strength at specific positions in the source antigen.

* Corresponding author. Mailing address: Division of Immunology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Phone: 81-52-764-2990. Fax: 81-52-764-2990. E-mail: kkuzushi{at}aichi-cc.jp.

Journal of Virology, January 2006, p. 883-890, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.883-890.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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