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* Clinic for Radiotherapy, University Hospital of Freiburg, Freiburg, Germany;
Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France;
Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Freiburg, Germany; and
Max-Planck Institute of Immunobiology, Freiburg, Germany
Tripeptidyl peptidase II (TPPII) is an oligopeptidase forming giant complexes in the cytosol that have high exo-, but also, endoproteolytic activity. Immunohistochemically, the complexes appear as distinct foci in the cytosol. In part controversial biochemical and functional studies have suggested that TPPII contributes, on the one hand, positively to Ag processing by generating epitope carboxyl termini or by trimming epitope precursors, and, on the other, negatively by destroying potentially antigenic peptides. To clarify which of these roles is predominant, we generated and analyzed TPPII-deficient mice. Cell surface levels of MHC class I peptide complexes tended to be increased on most cell types of these mice. Although presentation of three individual epitopes derived from lymphocytic choriomeningitis virus was not elevated on TPPII–/– cells, that of the immunodominant OVA epitope SIINFEKL was significantly enhanced. Consistent with this, degradation of a synthetic peptide corresponding to the OVA epitope and of another corresponding to a precursor thereof, both being proteasomally generated OVA fragments, was delayed in TPPII-deficient cytosolic extracts. In addition, dendritic cell cross-presentation of phagocytosed OVA and of OVA internalized as an immune complex was increased to about the same level as direct presentation of the Ag. The data suggest a moderate, predominantly destructive role of TPPII in class I Ag processing, in line with our finding that TPPII is not induced by IFN-
, which up-regulates numerous, predominantly constructive components of the Ag processing and presentation machinery.
1 This work was supported by the Deutsche Forschungsgemeinschaft (NI 368/4–2), the Clotten Foundation, and a grant from the Forschungskommission of the University of Freiburg Medical Faculty (NIE346/04).
2 E.F. and J.H. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Gabriele Niedermann, Clinic for Radiotherapy, University Hospital of D-79106 Freiburg, Freiburg, Germany. E-mail address: gabriele.niedermann{at}uniklinik-freiburg.de
4 Abbreviations used in this paper: ER, endoplasmic reticulum; Ct, C-terminal; ERAP, endoplasmic reticulum-associated aminopeptidase; LAP, leucine aminopeptidase; TOP, thimet oligopeptidase; PSA, puromycin sensitive aminopeptidase; TPPII, tripeptidyl peptidase II; KO, knockout; AAF-CMK alanine-alanine-phenylalanine-chloromethyl ketone; DCs, dendritic cells; BM, bone marrow; LCMV, lymphocytic choriomeningitis virus; VV, vaccinia virus; ID, immunodominant; WT, wild type.
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  J. Huai, E. Firat, A. Nil, D. Million, S. Gaedicke, B. Kanzler, M. Freudenberg, P. van Endert, G. Kohler, H. L. Pahl, et al. Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice PNAS, April 1, 2008; 105(13): 5177 - 5182. [Abstract] [Full Text] [PDF]
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