Modeling the MHC class I pathway by combining predictions of proteasomal cleavage,TAP transport and MHC class I binding

Tenzer, Stefan; Peters, Björn; Bulik, Sascha; Schoor, Oliver; Lemmel, Claudia; Schatz, Mark; Kloetzel, Peter M.; Rammensee, Hans Georg; Schild, Hansjörg; Holzhütter, Hermann−Georg

doi:10.1007/s00018-005-4528-2

Cited by 331 publications

(325 citation statements)

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“…We first determined the need for immunoproteasomal activity in the generation of the peptide Cp␣1 92-99 , one of the peptides that contribute to positive selection of OT-1 T cells (22). The use of proteasomal prediction programs (13) suggested that the generation of the Cp␣1 92-99 C terminus will be much more efficiently performed by immunoproteasomes (data not shown). This prediction was confirmed by the in vitro digestion of a N-and C-terminally extended Cp␣1 peptide (Cp␣1 86 -109 ) using purified constitutive proteasomes and immunoproteasomes followed by MS analysis and Edman sequencing for quantification of the fragments generated.…”

Section: Resultsmentioning

confidence: 99%

“…The specificity of this protease is influenced by the incorporation of three IFN-inducible ␤-subunits (␤1i, ␤2i, and ␤5i), which replace the three proteolytically active constitutive subunits (␤1, ␤2, and ␤5) during proteasome assembly, resulting in the formation of so-called immunoproteasomes (9,10). This type of proteasome generates reduced numbers of peptides with acid C termini and increased numbers of peptides with hydrophobic C termini (11,12), which is in favor of a more efficient transporter associated with antigen-presentation transport and binding to MHC class I molecules (13). In addition, a change in proteolytic specificity is apparent from the numerous examples reporting that either constitutive proteasomes or immunoproteasomes are required for the efficient generation of certain MHC class I ligands and consequently for the activation of CTL (14)(15)(16)(17)(18)(19).…”

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confidence: 99%

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Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses

Osterloh

Linkemann

Tenzer

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Differences in the cleavage specificities of constitutive proteasomes and immunoproteasomes significantly affect the generation of MHC class I ligands and therefore the activation of CD8-positive T cells. Based on these findings, we investigated whether proteasomal specificity also influences CD8-positive T cells during thymic selection by peptides derived from self proteins. We find that one of the self peptides responsible for positive selection of ovalbuminspecific OT-1 T cells, which is derived from the f-actin capping protein (Cp␣1), is efficiently generated only by immunoproteasomes. Furthermore, OT-1 mice backcrossed onto low molecular mass protein 7 (LMP7)-deficient mice show a 50% reduction of OT-1 cells. This deficiency is also observed after transfer of BM from OT-1 mice in LMP7-deficient mice and can be corrected by the injection of the Cp␣1 peptide. Interestingly, WT and LMP7-deficient mice mount comparable immune responses to the ovalbumin-derived epitope SIINFEKL. However, their cytotoxic T lymphocytes (CTL) differ in the use of T cell receptor V␤ genes. CTL derived from WT mice use V␤8 or V␤5 (the latter is also used by OT-1 cells), whereas SIINFEKL-specific CTL from LMP7-deficient mice are exclusively V␤8-positive. Taken together, our experiments provide strong evidence that proteasomal specificity shapes the repertoire of T cells participating in antigen-specific immune responses. selection ͉ T cell repertoire C ytotoxic T lymphocytes (CTL) recognize a complex of MHC class I molecules and peptides derived mainly from intracellular proteins. The generation of these peptides crucially depends on the activity of proteasomes, which represent the main proteolytic activity present in the cytoplasm and are responsible for the generation of the C termini of most peptides presented by MHC class I molecules (1-5). The 20S proteasome represents the proteolytic core complex, which is composed of seven different ␣-and seven different ␤-subunits organized in a complex of four stacked rings with ␣ 7 ␤ 7 ␤ 7 ␣ 7 stoichiometry (6-8). The specificity of this protease is influenced by the incorporation of three IFN-inducible ␤-subunits (␤1i, ␤2i, and ␤5i), which replace the three proteolytically active constitutive subunits (␤1, ␤2, and ␤5) during proteasome assembly, resulting in the formation of so-called immunoproteasomes (9, 10). This type of proteasome generates reduced numbers of peptides with acid C termini and increased numbers of peptides with hydrophobic C termini (11,12), which is in favor of a more efficient transporter associated with antigen-presentation transport and binding to MHC class I molecules (13). In addition, a change in proteolytic specificity is apparent from the numerous examples reporting that either constitutive proteasomes or immunoproteasomes are required for the efficient generation of certain MHC class I ligands and consequently for the activation of CTL (14-19). As a result, proteasomal specificities provide a major contribution to the hierarchies of epitopes recognized by pathog...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses

Osterloh

Linkemann

Tenzer

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…The latter efforts have led to the creation of algorithms that predict proteasome cleavage sites [90,91]. These algorithms have been combined with those for class I MHC peptide binding [92], and in some cases for TAP transport [93], to predict the peptide antigens most likely to be displayed. This approach has led to the successful identification of several antigens [94][95][96].…”

Section: The Impact Of Antigen Processing Pathways On the Display Of mentioning

confidence: 99%

The contributions of mass spectrometry to understanding of immune recognition by T lymphocytes

Engelhard

2007

International Journal of Mass Spectrometry

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Over the last 15 years, the ability of mass spectrometry to analyze complex peptide mixtures and identify individual species has provided unprecedented insights into the repertoire of peptide antigens displayed by MHC molecules and recognized by T lymphocytes. These include: understanding the peptide binding specificity of MHC molecules; understanding of roles of different intracellular components of the antigen processing pathways in determining the peptide display; and identification of a large number of individual peptide antigens associated with infectious diseases, cancer, and transplant rejection that have provided the basis for new immunologically based therapies. This review will summarize the impact that the application of mass spectrometry has had on these advances, with particular attention to the contributions of Professor Donald Hunt and members of his laboratory, and point out the opportunities for future work. Keywordsantigen processing; post-translational modification; peptides; MHC molecules THE NATURE OF ANTIGEN RECOGNITION BY T LYMPHOCYTEST lymphocytes are a branch of the immune system concerned with recognition of antigens that are displayed on the surface of host cells. These antigens are produced through intracellular proteolytic mechanisms that create small peptides, which are then rescued and presented at the cell surface by adaptor proteins called MHC molecules [reviewed in [1-6]. The binding site of each MHC molecule enables it to bind to a wide range of different peptides, and results in the display of a repertoire of such antigens, each recognized by a distinct T lymphocyte. This "antigen processing and presentation" mechanism results in the display of peptides derived from the proteins of pathogens that have infected the cell or been taken up by endocytosis. Their recognition by T lymphocytes results in the development of an immune response, and results in clearance of the pathogen and infected cells from the body. However, antigen processing and presentation pathways operate constitutively on normal cellular proteins as well, resulting in the display of peptide antigens that can be distinguished on tumors and transplanted tissues. Some of these "self-peptides" are also involved in the development of T lymphocytes in the thymus, and their recognition also controls the balance between selftolerance and autoimmune disease. Correspondence: phone: 434-924-2423; fax: 434-924-1221; email: vhe@virginia.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In most individuals, molecules of each MHC class are expressed from 3 genetic loci that ...

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“…158,159 It has been calculated from experimental digestion results, for instance, that the likelihood of a proteasomal cleavage after a lysine is very low, although a high number of (mainly HLA-A3 presented) epitopes own a C-terminal lysine. 144 This is suggestive for a supplementary enzyme system. 159 Thus, verification of in vitro proteasomal C-terminal generation predicts the intracellular generation of most class I ligands, but will miss those that are C-terminally liberated by other enzymes.…”

Section: Efficiency Of Reverse Immunologymentioning

confidence: 95%

“…In addition, an algorithm was developed that directly predicts CTL epitopes using large data sets of T-cell epitopes and nonepitopes as training data for the algorithm (CTLPred). 143 We concisely tested the performance of the five integrated algorithms (MHC-Pathway, 144 WAPP, 145 NetCTL, 146 IEDB and EpiJen 147 ) using as test-set the 64 nonameric peptides from our PRAME study that were in vitro tested for their HLA-A2 binding and proteasomal liberation to identify two CTL epitopes 119 ( Table 3). The two published epitopes were predicted in the 10 best ranked predicted epitopes by four of the five algorithms.…”

Section: Identification Of T-cell Epitopes For Cancer Immunotherapy Jmentioning

confidence: 99%

Identification of T-cell epitopes for cancer immunotherapy

2007

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The effectiveness of T-cell-mediated immunotherapy of cancer depends on both an optimal immunostimulatory context of the therapy and the proper selection with respect to quality and quantity of the targeted tumor-associated antigens (TAA), and, more precisely, the T-cell epitopes contained in these tumor proteins. Our progressing insight in human leukocyte antigen (HLA) class I and class II antigen processing and presentation mechanisms has improved the prediction by reverse immunology of novel cytotoxic T lymphocyte and T-helper cell epitopes within known antigens. Computer algorithms that in silico predict HLA class I and class II binding, proteasome cleavage patterns and transporter associated with antigen processing translocation are now available to expedite epitope identification. The advent of genomics allows a high-throughput screening for tumor-specific transcripts and mutations, with that identifying novel shared and unique TAA. The increasing power of mass spectrometry and proteomics will lead to the direct identification from the tumor cell surface of numerous novel tumor-specific HLA class I and class II presented ligands. Together, the expanded repertoire of tumor-specific T-cell epitopes will enable more precise immunomonitoring and the development of effective epitope-defined adoptive T-cell transfer and multi-epitope-based vaccination strategies targeting epitopes derived from a wider diversity of TAA presented in a broader array of HLA molecules.

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Modeling the MHC class I pathway by combining predictions of proteasomal cleavage,TAP transport and MHC class I binding

Cited by 331 publications

References 49 publications

Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses

Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses

The contributions of mass spectrometry to understanding of immune recognition by T lymphocytes

Identification of T-cell epitopes for cancer immunotherapy

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