MHCPred: a server for quantitative prediction of peptide-MHC binding

Guan, Peipei; Doytchinova, Irini; Zygouri, Christianna; Flower, Darren R.

doi:10.1093/nar/gkg510

Cited by 232 publications

(144 citation statements)

References 23 publications

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“…Therefore it would be useful to predict the MHC-presented peptides generated or destroyed by a given protease, such as CatS. The kinetic constants we determined for substrates with a distinct amino acid composition could be advantageous in predicting cleavage sites from the primary sequence of an antigen protein and could help to improve software for antigenic peptide prediction (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Quantifying Cathepsin S Activity in Antigen Presenting Cells Using a Novel Specific Substrate

Lützner

Kalbacher

2008

Journal of Biological Chemistry

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Cathepsin S (CatS) is a lysosomal cysteine protease belonging to the papain superfamily. Because of the relatively broad substrate specificity of this family, a specific substrate for CatS is not yet known. Based on a detailed study of the CatS endopeptidase specificity, using six series of internally quenched fluorescent peptides, we were able to design a specific substrate for CatS. The peptide series was based on the sequence GRWHTVGL-RWE-Lys(Dnp)-DArg-NH 2 , which shows only one single cleavage site between Gly and Leu and where every substrate position between P-3 and P-3 was substituted with up to 15 different amino acids. The endopeptidase specificity of CatS was mainly determined by the P-2, P-1, and the P-3 substrate positions. Based on this result, systematically modified substrates were synthesized. Two of these modified substrates, Mca-GRWPP-MGLPWE-Lys(Dnp)-DArg-NH 2 and Mca-GRWHPMGAPWELys(Dnp)-DArg-NH 2 , did not react with the purified cysteine proteases cathepsin B (CatB) and cathepsin L (CatL). Using a specific CatS inhibitor, we could further show that these two peptides were not cleaved by endosomal fractions of antigen presenting cells (APCs), when CatS was inhibited and related cysteine proteases cathepsin B, H, L and X were still active. Although aspartic proteases like cathepsin E and cathepsin D were also present, our substrates were suitable to quantify cathepsin S activity specifically in APCs, including B cells, macrophages, and dendritic cells without the use of any protease inhibitor. We find that CatS activity differs significantly not only between the three types of professional APCs but also between endosomal and lysosomal compartments.Lysosomal cysteine proteases of the papain family were long believed to be exclusively involved in nonspecific proteolysis within the lysosome. However, the use of specific protease inhibitors and the study of gene knock-out mice suggested that some of them are involved in many other processes, such as cellular homeostasis, autophagy, apoptosis, and antigen presentation (1-3). Antigen presentation by MHC 2 class II molecules requires the entry of antigens into the endosomal-lysosomal compartment. These antigens are then processed by proteolytic enzymes, of which the lysosomal cysteine proteases of the papain family constitute an important subset. The generated peptides bind to MHC class II molecules, which are then displayed at the surface of professional APCs including macrophages, dendritic cells (DCs), and B cells. The variety of MHC class II peptide products that can activate CD4 ϩ T cells is on the one hand determined by allelic variation in MHC molecule binding specificity and on the other by the identity and level of activity of processing proteases present in APCs. Although CatS is one of the major proteases involved in antigen processing (4 -6), specific determination of its activity in antigen presenting cells is currently complicated because a specific substrate is not yet known. One reason for this is that CatB, CatL, and CatS show relati...

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Section: Discussionmentioning

confidence: 99%

Quantifying Cathepsin S Activity in Antigen Presenting Cells Using a Novel Specific Substrate

Lützner

Kalbacher

2008

Journal of Biological Chemistry

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“…We evaluated a list of candidate peptides from lupus autoantigens that were previously identified in the literature (18)(19)(20) or identified as potential I-E k binders using an epitope prediction program (21) (Table S1). The peptide U1-70 131-150, hereinafter designated "U1-70," and the peptide U1-70 131-150 (P140), which is phosphorylated on serine residue 140, hereinafter "P140," demonstrated binding to I-E k in a competition assay with a moth cytochrome c (MCC) peptide (88-103), which binds I-E k (22) (Fig.…”

Section: Significancementioning

confidence: 99%

Tetramers reveal IL-17–secreting CD4⁺T cells that are specific for U1-70 in lupus and mixed connective tissue disease

Kattah

Newell

Jarrell

et al. 2015

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

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Antigen-specific CD4 + T cells are implicated in the autoimmune disease systemic lupus erythematosus (SLE), but little is known about the peptide antigens that they recognize and their precise function in disease. We generated a series of MHC class II tetramers of I-E k -containing peptides from the spliceosomal protein U1-70 that specifically stain distinct CD4 + T-cell populations in MRL/lpr mice. The T-cell populations recognize an epitope differing only by the presence or absence of a single phosphate residue at position serine 140 . The frequency of CD4 + T cells specific for U1-70(131-150):I-E k (without phosphorylation) correlates with disease severity and anti-U1-70 autoantibody production. These T cells also express RORγt and produce IL-17A. Furthermore, the U1-70-specific CD4 + T cells that produce IL-17A are detected in a subset of patients with SLE and are significantly increased in patients with mixed connective tissue disease. These studies provide tools for studying antigen-specific CD4 + T cells in lupus, and demonstrate an antigen-specific source of IL-17A in autoimmune disease.tetramer | autoimmunity | lupus | SLE | IL-17

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“…Binding of peptides to human leukocyte antigen (HLA)-A*0201 was predicted using 4 publicly available algorithms: ''BIMAS,'' ''LPpep,'' ''MHCPred'' and ''SYFPEITHI.'' [21][22][23][24] The peptides were ranked for each algorithm and sorted by a cumulative score. HLA-A*0201 peptide binding assay were conducted as described previously.…”

Section: Peptides and Peptide Predictionmentioning

confidence: 99%

The shared tumor associated antigen cyclin‐A2 is recognized by high‐avidity T‐cells

Kondo

Maecker

Draube

et al. 2009

Intl Journal of Cancer

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Cyclin-A2, a key cell cycle regulator, has been shown to be overexpressed in various types of malignancies with little expression in normal tissue. Such tumor-associated genes potentially are useful targets for cancer immunotherapy. However, high-avidity cyclinspecific T cells are considered to be thymically deleted. We identified at least one nonameric HLA-A*0201 binding cyclin-A2 epitope by a reverse immunology approach. Using a highly efficient T-cell expansion system that is based on CD40-activated B (CD40-B) cells as sole antigen-presenting cells we successfully generated cyclin-A2 specific CTL from HLA-A*0201 1 donors. Interestingly, high-avidity cyclin-A2 specific CTL lines, which recognized peptide-pulsed and antigen expressing target cells, were indeed generated by stimulation with CD40-B cells when pulsed with low concentrations of peptide, whereas CD40-B cells pulsed at saturating concentrations could only induce low-avidity CTL, which recognized peptide-pulsed target cells only. One high-avidity CTL line was subcloned and CTL clones, whose peptide concentration required for half-maximal lysis were less than 1 nM, could lyse cyclin-A2 expressing tumor cells. Taken together, cyclin A2 is an attractive candidate for immune intervention in a significant number of cancer patients and high-avidity T cells can be readily generated using CD40-B cells as antigen-presenting cells. ' 2009 UICC

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MHCPred: a server for quantitative prediction of peptide-MHC binding

Cited by 232 publications

References 23 publications

Quantifying Cathepsin S Activity in Antigen Presenting Cells Using a Novel Specific Substrate

Quantifying Cathepsin S Activity in Antigen Presenting Cells Using a Novel Specific Substrate

Tetramers reveal IL-17–secreting CD4⁺T cells that are specific for U1-70 in lupus and mixed connective tissue disease

The shared tumor associated antigen cyclin‐A2 is recognized by high‐avidity T‐cells

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MHCPred: a server for quantitative prediction of peptide-MHC binding

Cited by 232 publications

References 23 publications

Quantifying Cathepsin S Activity in Antigen Presenting Cells Using a Novel Specific Substrate

Quantifying Cathepsin S Activity in Antigen Presenting Cells Using a Novel Specific Substrate

Tetramers reveal IL-17–secreting CD4+T cells that are specific for U1-70 in lupus and mixed connective tissue disease

The shared tumor associated antigen cyclin‐A2 is recognized by high‐avidity T‐cells

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Tetramers reveal IL-17–secreting CD4⁺T cells that are specific for U1-70 in lupus and mixed connective tissue disease