Analysis of the Role of Tripeptidyl Peptidase II in MHC Class I Antigen Presentation In Vivo

Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
The Journal of Immunology (Impact Factor: 4.92). 11/2009; 183(10):6069-77. DOI: 10.4049/jimmunol.0803564
Source: PubMed


Previous experiments using enzyme inhibitors and RNA interference in cell lysates and cultured cells have suggested that tripeptidyl peptidase II (TPPII) plays a role in creating and destroying MHC class I-presented peptides. However, its precise contribution to these processes has been controversial. To elucidate the importance of TPPII in MHC class I Ag presentation, we analyzed TPPII-deficient gene-trapped mice and cell lines from these animals. In these mice, the expression level of TPPII was reduced by >90% compared with wild-type mice. Thymocytes from TPPII gene-trapped mice displayed more MHC class I on the cell surface, suggesting that TPPII normally limits Ag presentation by destroying peptides overall. TPPII gene-trapped mice responded as well as did wild-type mice to four epitopes from lymphocytic choriomeningitis virus. The processing and presentation of peptide precursors with long N-terminal extensions in TPPII gene-trapped embryonic fibroblasts was modestly reduced, but in vivo immunization with recombinant lentiviral or vaccinia virus vectors revealed that such peptide precursors induced an equivalent CD8 T cell response in wild-type and TPPII-deficient mice. These data indicate that while TPPII contributes to the trimming of peptides with very long N-terminal extensions, TPPII is not essential for generating most MHC class I-presented peptides or for stimulating CTL responses to several Ags in vivo.

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Available from: Diego J Farfán-Arribas, Feb 05, 2014
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    • "However, Their Tpp2 heterozygotes were leaner than their wild-type littermates, while their food intake was normal [24]. Gene-trapped disrupting Tpp2 mice with >90% reduced expression of TPPII compared to the wild-type mice were viable, fertile, and normal in appearance and behavior [25]. In contrast, knockout mice homozygotic for Tpp2−/− were viable and grossly indistinguishable from wide type littermates, but in these mice, TPPII deficiency activated cell type-specific death programs [26]. "
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    • "The main influence of TPPII on MHC class I processing is likely to be cytosolic destruction of epitopes, since data from two different types of TPPII-deficient mice show increased MHC class I expression [18] [27] "
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    • "In addition, it was proposed that TPPII trimming was essential because the proteasome always gave rise to too long peptides. However, a recent study in TPPII-knockdown mice demonstrated TPPII was indeed important (although not essential) for converting long peptides to shorter forms [52]. The peptide processing in the ER lumen is achieved by the aminopeptidase ERAP1 and ERAP2, which are capable of creating and destroying MHC ligands[53]. "
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