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Puromycin-Sensitive Aminopeptidase Limits MHC Class I Presentation in Dendritic Cells but Does Not Affect CD8 T Cell Responses during Viral Infections¹

Charles F. Towne^*, Ian A. York, Joost Neijssen, Margaret L. Karow, Andrew J. Murphy^¶, David M. Valenzuela^¶, George D. Yancopoulos^¶, Jacques J. Neefjes and Kenneth L. Rock^2,*

^* Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824; Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Amgen Incorporated, Thousand Oaks, CA 91320; and ^¶ Regeneron Pharmaceuticals Incorporated, Tarrytown, NY 10591

Previous experiments using enzyme inhibitors, cell lysates, and purified enzyme have suggested that puromycin-sensitive aminopeptidase (PSA) plays a role in creating and destroying MHC class I-presented peptides although its precise contribution to these processes is unknown. To examine the importance of this enzyme in MHC class I Ag presentation, we have generated PSA-deficient mice and cell lines from these animals. PSA-deficient mice are smaller and do not reproduce as well as wild type mice. In addition, dendritic cells from PSA-deficient mice display more MHC class I molecules on the cell surface, suggesting that PSA normally limits Ag presentation by destroying certain peptides in these key APCs. Surprisingly, MHC class I levels are not altered on other PSA-deficient cells and the processing and presentation of peptide precursors in PSA-deficient fibroblasts is normal. Moreover, PSA-deficient mice have normal numbers of T cells in the periphery, and respond as well as wild type mice to eight epitopes from three viruses. These data indicate that PSA may play a role in limiting MHC class I Ag presentation in dendritic cells in vivo but that it is not essential for generating most MHC class I-presented peptides or for stimulating CTL responses to several Ags.

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 work was support by a National Institutes of Health grant (to K.L.R.), and by National Institutes of Health Training Grant AI07349 (to C.F.T.). Core resources supported by the Diabetes Endocrinology Research Grant DK42520 were also used.

² Address correspondence and reprint requests to Dr. Kenneth Rock, University of Massachusetts Medical Center, Department of Pathology, Room S2-109, 55 Lake Avenue North, Worcester, MA 01655. E-mail address: Kenneth.Rock{at}umassmed.edu

³ Abbreviations used in this paper: MHC-I, MHC class I; ER, endoplasmic reticulum; TPPII, tripeptidyl peptidase II; LAP, leucine aminopeptidase; PSA, puromycin-sensitive aminopeptidase; BH, bleomycin hydrolase; VSV, vesicular stomatitis virus; KO, knock out; WT, wild type; SVNP, Sendai virus nucleoprotein; DC, dendritic cell.