The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/2/503/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 3, February 7, 2000 503-514

Original Article

Efficient Generation of a Hepatitis B Virus Cytotoxic T Lymphocyte Epitope Requires the Structural Features of Immunoproteasomes

Alice J.A.M. Sijtsa, Thomas Ruppertb, Barbara Rehermannc, Marion Schmidta, Ulrich Koszinowskib, and Peter-M. Kloetzela
a From the Institute of Biochemistry, Charité, Humboldt University Berlin, 10117 Berlin, Germany
b Max von Pettenkofer Institute, 80336 München, Germany
c Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Correspondence to: Peter-M. Kloetzel, Institute of Biochemistry, Charité, Humboldt University Berlin, Monbijoustrasse 2, 10117 Berlin, Germany. Tel:49-30-2802-6382 Fax:49-30-2802-6608 E-mail:P-M.Kloetzel{at}charite.de.

Interferon (IFN)-{gamma}–induced cells express the proteasome subunits low molecular weight protein (LMP)2, LMP7, and MECL-1 (multicatalytic endopeptidase complex–like 1), leading to the formation of immunoproteasomes. Although these subunits are thought to optimize MHC class I antigen processing, the extent of their role and the mechanistic aspects involved remain unclear. Herein, we study the proteolytic generation of an human histocompatibility leukocyte antigen (HLA)-Aw68–restricted hepatitis B virus core antigen (HBcAg) cytotoxic T lymphocyte (CTL) epitope that is recognized by peripheral blood lymphocytes from patients with acute self-limited but not chronic hepatitis B virus (HBV). Immunological data suggest that IFN-{gamma}–induced rather than uninduced HeLa cells process and present the HBV CTL epitope upon infection with HBcAg-expressing vaccinia viruses. Analyses of 20S proteasome digests of synthetic polypeptides covering the antigenic HBcAg peptide demonstrate that only immunoproteasomes efficiently perform the cleavages needed for the liberation of this HBV CTL epitope. Although the concerted presence of the three immunosubunits appears essential, we find that both catalytically active LMP7 and inactive LMP7 T1A support CTL epitope generation. We conclude that LMP7 influences the structural features of 20S proteasomes, thereby enhancing the activity of the LMP2 and MECL-1 catalytic sites, which provide cleavage specificity. Thus, LMP7 incorporation is of greater functional importance for the generation of an HBV CTL epitope than cleavage specificity.

Key Words: antigen processing, LMP7 T1A, hepatitis B virus, immunoproteasome, MHC class I


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