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

ABSTRACT 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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    ABSTRACT: Recent studies have identified Ca(2+) stores in sperm cells; however, it is not clear whether these Ca(2+) stores are functional and how they are mobilized. Here, in vitro and in vivo, we determined that tripeptidyl peptidase II antagonists strongly activated the cAMP/PKA signaling pathway that drives sperm capacitation-associated protein tyrosine phosphorylation. We demonstrated that in the absence of Ca(2+), TPIII antagonists elevated the intracellular Ca(2+) levels in sperm, resulting in a marked improvement in sperm movement, capacitation, acrosome reaction, and the in vitro fertilizing ability. This antagonist-induced release of intracellular Ca(2+) could be blocked by the inhibitors of ryanodine receptors (RyRs) which are the main intracellular Ca(2+) channels responsible for releasing stored Ca(2+). Consistent with these results, indirect immunofluorescence assay using anti-RyR antibodies further validated the presence of RyR3 in the acrosomal region of mature sperm. Thus, TPPII can regulate sperm maturation by modulating intracellular Ca(2+) stores via the type 3 RyR.
    PLoS ONE 06/2013; 8(6):e66634. DOI:10.1371/journal.pone.0066634 · 3.23 Impact Factor
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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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    ABSTRACT: The tripeptidyl-peptidase II complex consists of repeated 138 kDa subunits, assembled into two twisted strands that form a high molecular weight complex ( > 5 MDa). TPPII, like many other cytosolic peptidases, plays a role in the ubiquitin-proteasome pathway downstream of the proteasome as well as in the production and destruction of MHC class I antigens and degradation of neuropeptides. Tripeptidyl-peptidase II activity is increased in cells with an increased demand for protein degradation, but whether degradation of cytosolic peptides is the only cell biological role for TPPII has remained unclear. Recent data indicated that TPPII translocates into the nucleus to control DNA damage responses in malignant cells, supporting that cytosolic “housekeeping peptidases” may have additional roles in cell biology, besides their contribution to protein turnover. Overall, TPPII has an emerging importance in several cancer-related fields, such as metabolism, cell death control, and control of genome integrity; roles that are not understood in detail. The present paper reviews the cell biology of TPPII and discusses distinct roles for TPPII in the nucleus and cytosol.
    Journal of Oncology 08/2010; 2010(19). DOI:10.1155/2010/128478
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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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    ABSTRACT: Thus far, the best-studied and most appreciated biopolymers are the proteins. Although the investigation of proteins has been shown to be necessary for understanding of biological phenomena, more and more evidence shows that biological events cannot be explained solely by the functions of proteins. Fine tuning of the system requires the involvement of other biomolecules, such as carbohydrates and lipids. Key to our specific defense against microbial infections are critical interactions between the specific adaptive and relatively non-specific innate part of the immune response. The most critical link between both parts of the immune system is T cell activation by antigen presentation. This report describes the immunological significant role of bacterial-derived carbohydrate structures in T cell activation, as context of antigens as well as antigen itself. This report will expand the concepts of the role of carbohydrates in microbial interactions with the adaptive immune system.
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