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1
Wen, R., G. A. Cole, S. Surman, M. A. Blackman i D. L. Woodland. "Major histocompatibility complex class II-associated peptides control the presentation of bacterial superantigens to T cells." Journal of Experimental Medicine 183, nr 3 (1.03.1996): 1083–92. http://dx.doi.org/10.1084/jem.183.3.1083.
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Recent studies have shown that only a subset of major histocompatibility complex (MHC) class II molecules are able to present bacterial superantigens to T cells, leading to the suggestion that class-II associated peptides may influence superantigen presentation. Here, we have assessed the potential role of peptides on superantigen presentation by (a) analyzing the ability of superantigens to block peptide-specific T cell responses and (b) analyzing the ability of individual peptides to promote superantigen presentation on I-Ab-expressing T2 cells that have a quantitative defect in antigen processing. A series of peptides is described that specifically promote either toxic shock syndrome toxin (TSST) 1 or staphylococcal enterotoxin A (SEA) presentation. Whereas some peptides promoted the presentation of TSST-1 (almost 5,000-fold in the case of one peptide), other peptides promoted the presentation of SEA. These data demonstrate that MHC class II-associated peptides differentially influence the presentation of bacterial superantigens to T cells.
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Zandvliet, Maarten L., J. H. Frederik Falkenburg, Michel G. D. Kester, Arnoud H. de Ru, Peter A. van Veelen, Roelof Willemze, Henk-Jan Guchelaar i Pauline Meij. "Sequence Dependent Efficiency of Cross-Presentation in MHC Class I Requires Rational Design of Long Synthetic Peptides for Vaccination or Ex Vivo Activation". Blood 112, nr 11 (16.11.2008): 3904. http://dx.doi.org/10.1182/blood.v112.11.3904.3904.
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Abstract For the induction or boosting of antigen-specific CD8+ T cell responses, long synthetic peptides have been used in vaccination studies. Superior in vivo CD8+ T cell responses have been reported following vaccination with long peptides compared with minimal peptides, which was attributed to selective uptake and cross-presentation by professional antigen-presenting cells. Furthermore, to generate antigen-specific T cell lines for adoptive immunotherapy or to measure antigen-specific T cell responses, protein-spanning pools of overlapping long synthetic peptides can be used to simultaneously activate CD8+ and CD4+ T cells in peripheral blood mononuclear cells (PBMC) ex vivo. Although exogenous antigen is predominantly presented in MHC class II, it has been suggested that cross-presentation of long peptides in MHC class I can occur. However, the mechanism of cross-presentation of exogenous long peptides in MHC class I is not clear. Various models for cross-presentation have been described following uptake of soluble antigen in endosomes, among which antigen transport over the endosomal membrane followed by the classical proteasome- and TAP-dependent route, and entrance of MHC class I in the recycling endocytic MHC class II pathway where peptidase-trimmed exogenous antigens can exchange with peptides in the MHC class I molecules, resulting in TAP- and proteasome-independent cross-presentation. To improve the design of peptides for the in vivo or ex vivo activation of CD8+ T cells we investigated the mechanism and efficiency of cross-presentation of long peptides. We observed that antigen-presenting cells in peripheral blood, in particular monocytes, loaded with 15-mer peptides, 31-mer peptides or full length protein containing the NLV epitope were able to very efficiently induce IFNg production by cytomegalovirus (CMV) pp65 NLV-specific T cells. Specific T cells were most efficiently activated by N-terminally extended variants of the minimal epitope, while the use of C-terminally extended variants resulted in a 10-fold reduction of activation efficiency. Purification of these antigens by high performance liquid chromatography (HPLC) followed by mass spectrometry demonstrated that activation was not caused by contamination with the minimal epitope sequence. Also CD8+ T cells specific for other CMV and minor histocompatibility antigen (mHag) epitopes were activated by monocytes loaded with 15-mer or 20-mer peptides. Again N-terminally extended variants of minimal epitopes very efficiently induced activation, while the use of C-terminally variants or full length protein resulted in highly variable efficiency of activation, ranging from 10-fold reduction to complete absence of activation. Interestingly, TAP-deficient T2 cells loaded with CMV pp65 NLV antigens also efficiently activated NLV-specific T cells, indicating that the route of presentation was TAP-independent. Addition of lactacystin during loading of monocytes with CMV pp65 NLV 15-mer did not affect activation of specific T cells, suggesting that cross-presentation was proteasome-independent. Addition of primaquine reduced activation of specific T cells by the NLV 15-mer peptide, but not by the minimal NLV 9-mer peptide, suggesting that cross-presentation was dependent on endosomal recycling. To compare cross-presentation with presentation of endogenously synthesized antigen, TAP-competent T1 and TAP-deficient T2 cells were retrovirally transduced with the CMV pp65 gene. CMV pp65-specific T cells were activated by CMV pp65 transduced T1 but not T2 cells, indicating that endogenously synthesized CMV pp65 required processing and presentation by the classical proteasome- and TAP-dependent route. These data suggest that long synthetic peptides can be processed by peptidases in endocytic compartments and presented by recycling MHC class I molecules. Not all immunogenic epitopes that have been selected in vivo for efficient processing and presentation by the classical pathway may be presented efficiently by cross-presentation. As the efficiency of cross-presentation of long synthetic peptides may depend on the sequence of the C-terminal extension, a rational design of peptides is crucial for efficient activation of CD8+ T cells in approaches of vaccination, adoptive transfer and immune monitoring.
3
Utz, U., S. Koenig, J. E. Coligan i W. E. Biddison. "Presentation of three different viral peptides, HTLV-1 Tax, HCMV gB, and influenza virus M1, is determined by common structural features of the HLA-A2.1 molecule." Journal of Immunology 149, nr 1 (1.07.1992): 214–21. http://dx.doi.org/10.4049/jimmunol.149.1.214.
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Abstract To determine whether similar or dissimilar molecular features of class I molecules are involved in the presentation of structurally distinct peptides, we have investigated the influence of different pockets of the HLA-A2.1 molecule on the presentation of three different viral peptides. HTLV-I Tax peptide 12-19, HCMV gB 619-628, and influenza M1 58-66 are minimal peptides that induce HLA-A2.1-restricted noncross-reactive CTL. A detailed analysis of the structural features of HLA-A2.1 that are involved in peptide presentation was undertaken using a panel of 11 HLA-A2 mutants with single amino acid substitutions within pockets present in the peptide binding site. Nine of the 11 mutants affected presentation of each of the three peptides, whereas the other two mutants had negative effects on presentation of only two of these viral peptides. These results indicate that common structural features in HLA-A2 determine the binding of different peptides, and help to provide a plausible explanation for how structurally diverse peptides bind to HLA-A2.
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Fremont, Daved H., Shaodong Dai, Herbert Chiang, Frances Crawford, Philippa Marrack i John Kappler. "Structural Basis of Cytochrome c Presentation by IEk". Journal of Experimental Medicine 195, nr 8 (15.04.2002): 1043–52. http://dx.doi.org/10.1084/jem.20011971.
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The COOH-terminal peptides of pigeon and moth cytochrome c, bound to mouse IEk, are two of the most thoroughly studied T cell antigens. We have solved the crystal structures of the moth peptide and a weak agonist–antagonist variant of the pigeon peptide bound to IEk. The moth peptide and all other peptides whose structures have been solved bound to IEk, have a lysine filling the p9 pocket of IEk. However, the pigeon peptide has an alanine at p9 shifting the lysine to p10. Rather than kinking to place the lysine in the anchor pocket, the pigeon peptide takes the extended course through the binding groove, which is characteristic of all other peptides bound to major histocompatibility complex (MHC) class II. Thus, unlike MHC class I, in which peptides often kink to place optimally anchoring side chains, MHC class II imposes an extended peptide conformation even at the cost of a highly conserved anchor residue. The substitution of Ser for Thr at p8 in the variant pigeon peptide induces no detectable surface change other than the loss of the side chain methyl group, despite the dramatic change in recognition by T cells. Finally, these structures can be used to interpret the many published mutational studies of these ligands and the T cell receptors that recognize them.
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Hombach, J., H. Pircher, S. Tonegawa i R. M. Zinkernagel. "Strictly transporter of antigen presentation (TAP)-dependent presentation of an immunodominant cytotoxic T lymphocyte epitope in the signal sequence of a virus protein." Journal of Experimental Medicine 182, nr 5 (1.11.1995): 1615–19. http://dx.doi.org/10.1084/jem.182.5.1615.
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Peptides presented by major histocompatibility complex (MHC) class I molecules are derived from intracellularly synthesized proteins. Cytosolic proteins are fragmented into peptides, which are subsequently transported via the transporter of antigen presentation (TAP) into the endoplasmic reticulum (ER), where they bind to MHC class I molecules. We have investigated the requirements for MHC class I presentation of the immunodominant gp33 cytotoxic T lymphocyte epitope of the lymphocytic choriomeningitis virus. This epitope is located within the leader peptide of the virus glycoprotein. Such an epitope is expected to be presented in a TAP-independent manner, since it is released into the ER by signal peptidase. Taking advantage of TAP1-/- mice, however, we show both in vitro and in vivo that, after virus infection, the presentation of the gp33 epitope is strictly dependent on a functional TAP heterodimer. The results are discussed with respect to peptide trimming processes in the ER.
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Neisig, A., J. Roelse, A. J. Sijts, F. Ossendorp, M. C. Feltkamp, W. M. Kast, C. J. Melief i J. J. Neefjes. "Major differences in transporter associated with antigen presentation (TAP)-dependent translocation of MHC class I-presentable peptides and the effect of flanking sequences." Journal of Immunology 154, nr 3 (1.02.1995): 1273–79. http://dx.doi.org/10.4049/jimmunol.154.3.1273.
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Abstract The MHC-encoded transporter associated with Ag presentation (TAP) translocates peptides from the cytosol to the ER lumen, where association with MHC class I molecules occurs. The MHC class I/peptide complex is subsequently transported to the cell surface for presentation to CD8+T cells. We studied TAP-dependent translocation of defined MHC class I presentable murine peptides by competition for translocation of a radiolabeled model peptide, to address whether efficient peptide presentation by MHC class I molecules is preceded by equal efficient peptide translocation by TAP. Surprisingly, we observed that four immunodominant viral peptides of 16 peptides tested were very inefficiently transported by TAP. Inefficient translocation could be overcome by substitution of a proline residue present at position 3 in the peptides. Furthermore, addition of natural flanking amino acids directly surrounding a poorly transported peptide could considerably improve translocation by TAP. Our data suggest that some peptides are efficiently transported by TAP in their optimal size for MHC class I binding, whereas other peptides are transported as larger peptide fragments that need further trimming in the ER for MHC class I binding.
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Daniel, Soizic, Vladimir Brusic, Sophie Caillat-Zucman, Nicolai Petrovsky, Leonard Harrison, Daniela Riganelli, Francesco Sinigaglia, Fabio Gallazzi, Jürgen Hammer i Peter M. van Endert. "Relationship Between Peptide Selectivities of Human Transporters Associated with Antigen Processing and HLA Class I Molecules". Journal of Immunology 161, nr 2 (15.07.1998): 617–24. http://dx.doi.org/10.4049/jimmunol.161.2.617.
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Abstract Efficiency of presentation of a peptide epitope by a MHC class I molecule depends on two parameters: its binding to the MHC molecule and its generation by intracellular Ag processing. In contrast to the former parameter, the mechanisms underlying peptide selection in Ag processing are poorly understood. Peptide translocation by the TAP transporter is required for presentation of most epitopes and may modulate peptide supply to MHC class I molecules. To study the role of human TAP for peptide presentation by individual HLA class I molecules, we generated artificial neural networks capable of predicting the affinity of TAP for random sequence 9-mer peptides. Using neural network-based predictions of TAP affinity, we found that peptides eluted from three different HLA class I molecules had higher TAP affinities than control peptides with equal binding affinities for the same HLA class I molecules, suggesting that human TAP may contribute to epitope selection. In simulated TAP binding experiments with 408 HLA class I binding peptides, HLA class I molecules differed significantly with respect to TAP affinities of their ligands. As a result, some class I molecules, especially HLA-B27, may be particularly efficient in presentation of cytosolic peptides with low concentrations, while most class I molecules may predominantly present abundant cytosolic peptides.
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Mo, X. Y., Paolo Cascio, Kristen Lemerise, Alfred L. Goldberg i Kenneth Rock. "Distinct Proteolytic Processes Generate the C and N Termini of MHC Class I-Binding Peptides". Journal of Immunology 163, nr 11 (1.12.1999): 5851–59. http://dx.doi.org/10.4049/jimmunol.163.11.5851.
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Abstract Most of the MHC class I peptides presented to the immune system are generated during the course of protein breakdown by the proteasome. However, the precise role of the proteasome, e.g., whether this particle or some other protease generates the carboxyl (C) and amino (N) termini of the presented 8- to 10-residue peptides, is not clear. Here, we show that presentation on Db of ASNENMETM, a peptide from influenza nucleoprotein, and on Kb of FAPGNYPAL, a peptide from Sendai virus nucleoprotein, was blocked by the proteasome inhibitor, lactacystin. Using plasmid minigene constructs encoding oligopeptides of various lengths, we found that presentation of ASNENMETM from C-terminally extended peptides that contain this antigenic peptide plus three or five additional amino acids and presentation of FAPGNYPAL from a peptide containing FAPGNYPAL plus one additional C-terminal residue required the proteasome. In contrast, the proteasome inhibitor did not reduce presentation of cytosolically expressed ASNENMETM or FAPGNYPAL or N-terminally extended versions of these peptides, suggesting involvement of aminopeptidase(s) in trimming these N-extended variants. Accordingly, when the N termini of these 3N-extended peptides were blocked by acetylation, they were resistant to hydrolysis by cellular aminopeptidases and pure leucine aminopeptidase. Moreover, if introduced into the cytosol, Ag presentation of these peptides occurred to a much lesser extent than from their nonacetylated counterparts. Thus, the proteasome is essential for the generation of ASNENMETM and FAPGNYPAL peptides from the full-length nucleoproteins. Although it generates the C termini of these presented peptides, distinct aminopeptidase(s) can trim the N termini of these presented peptides to their proper size.
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Monji, T., i D. Pious. "Exogenously provided peptides fail to complex with intracellular class II molecules for presentation by antigen-presenting cells." Journal of Immunology 158, nr 7 (1.04.1997): 3155–64. http://dx.doi.org/10.4049/jimmunol.158.7.3155.
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Abstract Exogenously supplied antigenic peptides can bind to and be presented by cell surface class II molecules of APCs without prior processing. However, it has been unclear whether peptide Ags exogenously supplied to APCs can also form complexes with nascent intracellular class II molecules that contribute to Ag presentation. We found that exogenously provided peptide Ags, unlike whole protein Ags, are presented as efficiently by fixed as by unfixed B lymphoblastoid APCs, suggesting that intracellular processes do not contribute to the presentation of exogenously supplied peptides by unfixed APCs. Consistent with this finding, exogenously provided peptides do not bind detectably to nascent intracellular class II molecules. We studied the basis for this failure. First, as compared with whole proteins, exogenously supplied peptides accumulate very poorly intracellularly. Second, peptides are more rapidly exocytosed. The limited ability of APCs to accumulate exogenously supplied peptides intracellularly provides a likely explanation for the failure of these peptides to associate with nascent intracellular class II molecules. Exogenously supplied peptides probably never reach the intracellular vesicles in which peptide loading of class II molecules occurs. These findings have implications for the use of peptides therapeutically to block presentation of autoantigens in autoimmune disease.
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Stryhn, A., L. O. Pedersen, T. Romme, A. C. Olsen, M. H. Nissen, C. J. Thorpe i S. Buus. "pH dependence of MHC class I-restricted peptide presentation." Journal of Immunology 156, nr 11 (1.06.1996): 4191–97. http://dx.doi.org/10.4049/jimmunol.156.11.4191.
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Abstract The function of MHC class I molecules is to bind and present antigenic peptides to cytotoxic T cells. Here, we report that class I-restricted peptide presentation is strongly pH dependent. The presentation of some peptides was enhanced at acidic pH, whereas the presentation of others was inhibited. Biochemical peptide-MHC class I binding assays demonstrated that peptide-MHC class I complexes are more stable at neutral pH than at acidic pH. We suggest that acid-dependent peptide dissociation can generate empty class I molecules and that the resulting binding potential can be exploited by a subset of peptide-MHC class I combinations, in some cases leading to considerable peptide exchange. We further speculate that the relative instability of peptide-class I complexes under acidic conditions may affect the outcome of class I-restricted Ag presentation, as less stably associated peptides may dissociate from class I during passage of the acidic trans-Golgi network, and therefore may not be presented. Finally, our results may in part explain how endocytosed proteins can be presented by MHC class I molecules to cytotoxic T cells.
11
Boucau, Julie, Julien Madouasse, Christopher Carlin, Tom Zhu, Yang Xu, Mariko Shimada i Sylvie Le Gall. "Effect of cellular activation on the antigen processing machinery of primary CD4 T cells. (P5029)". Journal of Immunology 190, nr 1_Supplement (1.05.2013): 110.15. http://dx.doi.org/10.4049/jimmunol.190.supp.110.15.
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Abstract The killing of HIV-infected CD4 T cells by specific CD8 T cells (CTL) requires the presentation of peptide-MHC-I complexes produced during the intracellular degradation of viral proteins by the proteasome and other peptidases, to their cognate T cell receptors. HIV infection induces general cellular activation, which renders cells more susceptible to infection. Whether the activation state of cells alters the expression and activity of the antigen processing machinery and the kinetics and nature of epitopes displayed by MHC-I is not known despite its potential role in altering the efficiency of recognition of infected cells by CTL. We compared the expression and peptidase activities of the antigen processing machinery of primary CD4 T cells upon activation with anti-CD3/CD28 beads or with phytohemagglutinin. In primary CD4 T cells from HIV seronegative individuals, the hydrolytic activities of the proteasome, the expression of several of its subunits and of the peptidase TPP2 significantly increased upon activation. The mass spectrometry analysis of in vitro degradation of 2 long epitope-containing HIV peptides in extracts from CD3/CD28-activated CD4 T cells showed production of smaller and less antigenic peptides than in the non-activated samples. Reduced presentation of peptides by activated cells might lead to reduced recognition and slower clearance of activated infected cells by CTL thus allowing more time for viral replication and spread.
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Garstka, Malgorzata A., Alexander Fish, Patrick H. N. Celie, Robbie P. Joosten, George M. C. Janssen, Ilana Berlin, Rieuwert Hoppes i in. "The first step of peptide selection in antigen presentation by MHC class I molecules". Proceedings of the National Academy of Sciences 112, nr 5 (20.01.2015): 1505–10. http://dx.doi.org/10.1073/pnas.1416543112.
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MHC class I molecules present a variable but limited repertoire of antigenic peptides for T-cell recognition. Understanding how peptide selection is achieved requires mechanistic insights into the interactions between the MHC I and candidate peptides. We find that, at first encounter, MHC I H-2Kb considers a wide range of peptides, including those with expanded N termini and unfitting anchor residues. Discrimination occurs in the second step, when noncanonical peptides dissociate with faster exchange rates. This second step exhibits remarkable temperature sensitivity, as illustrated by numerous noncanonical peptides presented by H-2Kb in cells cultured at 26 °C relative to 37 °C. Crystallographic analyses of H-2Kb–peptide complexes suggest that a conformational adaptation of H-2Kb drives the decisive step in peptide selection. We propose that MHC class I molecules consider initially a large peptide pool, subsequently refined by a temperature-sensitive induced-fit mechanism to retain the canonical peptide repertoire.
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Yin, Liusong, Mauricio Calvo-Calle i Lawrence Stern. "Characterization of HLA-DM susceptibility of MHC II-peptide complex in antigen presentation and epitope selection (100.54)". Journal of Immunology 186, nr 1_Supplement (1.04.2011): 100.54. http://dx.doi.org/10.4049/jimmunol.186.supp.100.54.
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Abstract HLA-DM (DM) is a non-classic major histocompatibility complex II (MHC II), which mediates the exchange of peptides loading to MHC II during antigen presentation. However, the role of DM-mediated peptide exchange in epitope selection is still unclear. In this study, we addressed this question systematically using overlapping peptides from vaccinia virus protein A10L. We measured the binding affinity, intrinsic half life, DM-mediated half life and immunogenecity of 126 A10L peptides bound to HLA-DR1. Correlation coefficient analysis shows that immunogenecity of peptides is very weakly correlated with either binding affinity or intrinsic half life, while strongly correlating with half life in the presence of DM. Moreover, receiver operating characteristics analysis (ROC) indicates that DM-mediated half life is a very strong predictor for epitopes, while binding affinity and intrinsic half life can only mildly predicts epitopes. Taken together, our present quantitative and qualitive analysises demonstrate that DM-susceptibility is a strong and independent factor governing peptide’s immunogenicity.
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Barouch, D., T. Friede, S. Stevanović, L. Tussey, K. Smith, S. Rowland-Jones, V. Braud, A. McMichael i H. G. Rammensee. "HLA-A2 subtypes are functionally distinct in peptide binding and presentation." Journal of Experimental Medicine 182, nr 6 (1.12.1995): 1847–56. http://dx.doi.org/10.1084/jem.182.6.1847.
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Nearly half of HLA-A2-positive individuals in African populations have a subtype of HLA-A2 other than the A*0201 allele. We have isolated the common African HLA-A2 subtype genes from Epstein-Barr virus-transformed B cell lines and have established stable class I reduced transfectants expressing these alleles. We have studied the peptide binding and presentation properties of A*0201, A*0202, A*0205, A*0214, and A*6901 by a combination of approaches: assaying direct binding of labeled synthetic peptides, studying the ability of antigen-specific cytotoxic T lymphocytes to recognize peptide-pulsed cells, and sequencing peptide pools and individual ligands eluted from cells. We find that A*0201-restricted peptides can also bind to A*0202 but do not bind strongly to the other alleles in this study. We show that some cytotoxic T lymphocytes can recognize all subtypes capable of binding an antigenic peptide, whereas others are subtype specific. Sequencing of eluted peptides reveals that A*0202 has a similar peptide motif to A*0201, but that A*0205, A*0214, and A*6901 have different motifs. These data strongly support a model in which residue 9 (Phe or Tyr) of the A2/A68/A69 molecules is a critical factor in determining the specificity of the B pocket of the major histocompatibility complex and the position 2 anchor residue of associated peptides. We conclude that a single-amino acid difference in the major histocompatibility complex can be sufficient to cause a dramatic change in the nature of bound peptides, implying that individuals with closely related HLA subtypes may present very different repertoires of antigenic peptides to T cells in an immune response. It is likely to be a general phenomenon that very similar class I subtypes will behave as functionally distinct HLA allotypes.
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Anton, L. C., J. W. Yewdell i J. R. Bennink. "MHC class I-associated peptides produced from endogenous gene products with vastly different efficiencies." Journal of Immunology 158, nr 6 (15.03.1997): 2535–42. http://dx.doi.org/10.4049/jimmunol.158.6.2535.
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Abstract We compared the efficiency of generating antigenic peptides from various polypeptide contexts expressed by recombinant vaccinia viruses. These included full-length influenza virus nucleoprotein (NP(1-498)), two truncated forms, and cytosolic and endoplasmic reticulum-targeted minimal peptides. Two peptides were studied, NP(50-57) (Kk-restricted) and NP(147-155) (Kd-restricted). The efficiency of peptide generation was measured in cytotoxicity assays by determining 1) the kinetics of presentation following infection using brefeldin A to block additional presentation and 2) the concentration of anti-class I mAbs required to block presentation. The two determinants behaved similarly, being presented most efficiently from minigene products, with intermediate efficiency from fragments, and least efficiently from NP(1-498). Direct quantitation of HPLC-purified peptides supported the validity of these simple methods to roughly estimate the efficiency of class I Ag presentation. It also surprisingly revealed that 60- to 90-fold more NP(50-57) than NP(147-155) peptide was present in cells expressing NP(1-498) or a rapidly degraded fragment (for NP(1-498), 1800 peptides/cell of NP(50-57) vs 30 peptides/cell of NP(147-155)). By contrast, nearly identical (and much greater) amounts of peptides were recovered from cells expressing minigene products (55,000 copies of either peptide/cell). These findings demonstrate 1) that immunodominant peptides from the same protein can be generated with vastly different efficiencies, and 2) that cytosolic or endoplasmic reticulum-targeted minigene products are presented far more efficiently than longer polypeptides.
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Legge, Kevin L., Booki Min, Christopher Pack, Jacque Caprio i Habib Zaghouani. "Differential Presentation of an Altered Peptide Within Fetal Central and Peripheral Organs Supports an Avidity Model for Thymic T Cell Development and Implies a Peripheral Readjustment for Activation". Journal of Immunology 162, nr 10 (15.05.1999): 5738–46. http://dx.doi.org/10.4049/jimmunol.162.10.5738.
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Abstract Altered self peptides may drive T cell development by providing avidity of interactions low enough to potentiate positive selection but not powerful enough to trigger programmed cell death. Since the peptide repertoire in both central and peripheral organs is nearly the same, interactions of these peptides with T cells in the thymus would have to be different from those taking place in the periphery; otherwise, T cell development and maturation would result in either autoimmunity or T cell deficiency. Herein, a self and an altered self peptide were delivered to fetuses, and their presentation as well as the consequence of such presentation on T cell development were assessed. The results indicate that the self peptide was presented in both central and peripheral fetal organs and that such presentation abolished T cell responses to both peptides during adult life. However, the altered peptide, although presented in vivo as well as in vitro by splenic cells, was unable to stimulate a specific T cell clone when the presenting cells were of thymic origin and allowed offspring to be responsive to both peptides. These findings indicate that central and peripheral organs accommodate selection and peripheral survival of T cells by promoting differential altered peptide presentation.
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Balasubramani, Anand. "Stitching peptides for presentation". Science 362, nr 6412 (18.10.2018): 300.20–302. http://dx.doi.org/10.1126/science.362.6412.300-t.
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Heemels, Marie-Thérèse, i Hidde Ploegh. "Antigen presentation: Untapped peptides". Current Biology 3, nr 6 (czerwiec 1993): 380–83. http://dx.doi.org/10.1016/0960-9822(93)90208-6.
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Bell, Elaine. "Trimming peptides for presentation". Nature Reviews Immunology 6, nr 1 (styczeń 2006): 7. http://dx.doi.org/10.1038/nri1765.
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Lind, Kristin, Hernando Escobar, Eduardo Reyes-Vargas, Julio Delgado i Nilabh Shastri. "ERAAP-deficiency differentially affects peptide presentation across multiple MHC I (100.15)". Journal of Immunology 186, nr 1_Supplement (1.04.2011): 100.15. http://dx.doi.org/10.4049/jimmunol.186.supp.100.15.
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Abstract Genome-wide association studies in humans have linked polymorphisms in the ER aminopeptidase associated with antigen processing (ERAAP) as well as particular MHC class I molecules to autoimmune diseases. How ERAAP polymorphisms affect function of different MHC I molecules is not known. ERAAP normally trims antigenic precursor peptides to generate potential peptide-MHC I ligands that can be recognized by CD8 T cells. To detect changes in the peptide repertoires displayed by different MHC I molecules, we immunized wild-type B10.D2 (H-2d) mice with ERAAP-deficient (ERAAP-KO) cells and analyzed the specificity of the CD8 T cell response. In wild-type mice, anti-ERAAP KO T cells responded primarily to peptides presented by Kd, and not the other two MHC I molecules, Dd and Ld of the H-2d haplotype. We also assessed the MHC I bound peptide repertoire by mass spectrometry. This analysis revealed that Dd and Kd molecules were bound to large number of shared as well as unique peptides, some with N-terminal extensions. Remarkably, Ld bound peptides were not detected in ERAAP-deficient mice. Thus, changes in ERAAP expression can have a major influence on the peptide repertoire presented by different MHC I molecules as well as on CD8 T cell responses.
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Khodadoust, Michael, Niclas Olsson, Lisa Wagar, Binbin Chen, Keith Rawson, Chih Long Liu, David Steiner i in. "Antigen Presentation Profiling Reveals T-Cell Recognition of Lymphoma Immunoglobulin Neoantigens". Blood 128, nr 22 (2.12.2016): 915. http://dx.doi.org/10.1182/blood.v128.22.915.915.
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Abstract Neoantigens arising through somatic mutations are increasingly recognized as key tumor antigens driving clinical immune responses. We sought to identify human lymphoma neoantigens through a genomic and proteomic characterization of peptide ligands of major histocompatibility complex class I (MHC-I) and class II (MHC-II) of a cohort of patients with untreated mantle cell lymphoma. Peptide identification was performed through analysis of MHC-I and MHC-II peptide ligands using liquid chromatography and tandem mass spectrometry (LC/MS-MS), and augmented by generating patient-specific proteome databases through tumor:normal whole exome sequencing and targeted immunoglobulin gene sequencing in 17 patients. A total of 66 neoantigen peptides from 9 patients were found to be presented by MHC, and surprisingly all neoantigenic peptides were derived from either the lymphoma immunoglobulin heavy or light chain genes. There was no detectable MHC presentation of hundreds of candidate somatic neoantigenic peptides from other genes despite widespread antigen presentation of the proteome including proteins encoded by germline heterozygous single nucleotide polymorphisms. Clonotypic lymphoma immunoglobulin sequences were among the most commonly presented proteins by both MHC-I and MHC-II, yet MHC-I presentation of variable regions was nearly absent and included only a single neoantigen derived from IGVH. In contrast, the variable region was frequently presented by MHC-II and included neoantigen peptides created through somatic hypermutation or VDJ recombination. Autologous circulating T-cells specific for immunoglobulin-derived neoantigens could be detected using MHC-II tetramers and their frequency dynamically changed with vaccination and therapy. These findings suggest that immunoglobulin derived neoantigens are frequently presented by lymphoma, and represent potential targets for CD4, but not CD8, T-cell mediated therapies. Figure. MHC-I and MHC-II presentation of lymphoma immunoglobulin. (A) MHC-I (left) and MHC-II (right) presented peptides derived from patients' immunoglobulin were mapped to the immunoglobulin domains. Peptides recovered from all seventeen patients are mapped to a schematic of the IgM molecule with a heat map indicating the number of recovered peptides covering each position. (B) Expanded view of the immunoglobulin heavy chain variable region. The heatmap represents the total number of MHC-presented peptides that span that position, including non-neoantigens for MHC-I (above) and MHC-II (below). Neoantigen peptides created by either somatic hypermutation or VDJ rearrangement are mapped above or below the heat map. Red, positions within the recovered peptides which are altered from germline variable genes thus creating neoantigens. Boxes, peptides derived from a single patient. Figure. MHC-I and MHC-II presentation of lymphoma immunoglobulin. (A) MHC-I (left) and MHC-II (right) presented peptides derived from patients' immunoglobulin were mapped to the immunoglobulin domains. Peptides recovered from all seventeen patients are mapped to a schematic of the IgM molecule with a heat map indicating the number of recovered peptides covering each position. (B) Expanded view of the immunoglobulin heavy chain variable region. The heatmap represents the total number of MHC-presented peptides that span that position, including non-neoantigens for MHC-I (above) and MHC-II (below). Neoantigen peptides created by either somatic hypermutation or VDJ rearrangement are mapped above or below the heat map. Red, positions within the recovered peptides which are altered from germline variable genes thus creating neoantigens. Boxes, peptides derived from a single patient. Disclosures Newman: Roche: Consultancy. Carlton:Adaptive Biotechnologies: Employment, Equity Ownership. Moorhead:Adaptive Biotechnologies: Employment. Faham:Adaptive Biotechnologies Corp: Employment.
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Prasad, Sharanya, Shelley Starck i Nilabh Shastri. "Presentation of cryptic peptides by MHC I molecules is enhanced by inflammatory stimuli. (P5003)". Journal of Immunology 190, nr 1_Supplement (1.05.2013): 110.2. http://dx.doi.org/10.4049/jimmunol.190.supp.110.2.
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Abstract Cytolytic T cells eliminate infected cells by recognizing intracellular peptides presented by MHC class I molecules. The antigenic peptides are derived primarily from newly synthesized proteins including those produced by cryptic translation. Previous studies have shown that in addition to the canonical AUG codon, translation can be initiated at non-AUG codons . Furthermore, translation initiation at non-AUG codons such as CUG is mechanistically distinct from canonical translation initiation as it is resistant to protein synthesis inhibitors that cause global translation shutdown. Here, we show that Toll-like receptor (TLR) signaling pathways involved in pathogen recognition enhance presentation of the cryptic peptides. Moreover, infection of bone-marrow derived macrophages with MCMV, influenza viruses or pro-inflammatory cytokines also enhances cryptic peptide presentation. Thus, translation and presentation of cryptic peptides may allow the immune system to detect intracellular pathogens that inhibit host translation and presentation of peptides from conventional sources.
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Lo-Man, Richard, Jan P. M. Langeveld, Pierre Martineau, Maurice Hofnung, Robert H. Meloen i Claude Leclerc. "Immunodominance Does Not Result from Peptide Competition for MHC Class II Presentation". Journal of Immunology 160, nr 4 (15.02.1998): 1759–66. http://dx.doi.org/10.4049/jimmunol.160.4.1759.
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Abstract Competition for binding to MHC class II molecules between processed peptides derived from a single protein Ag is considered an important parameter leading to the presentation of a limited set of peptides by APCs. We tested the relevance of this competition process in a model Ag, the MalE protein, by deleting T cell epitopes or by introducing a competitor T cell peptide. We identified in DBA/1 (I-Aq) mice six immunodominant T cell determinants in the MalE sequence, 89–95, 116–123, 198–205, 211–219, 274–281, and 335–341. Synthetic peptides carrying these determinants were classified in three groups as weak, intermediate, or strong I-Aq binders in competition experiments with the PreS:T peptide of hepatitis B surface Ag. In vivo, synthetic MalE peptides with weak and intermediate MHC binding capacity were inhibited in their capacity to stimulate proliferative response in the presence of the PreS:T competitor peptide, whereas the strongest MHC binder was not. Strikingly, the insertion of the potent competitor PreS:T peptide into the MalE sequence, as a single copy or as four copies, did not inhibit the proliferative response to the six immunodominant peptides of the recipient protein. Moreover, deletion in the protein sequence disrupting either the weak (198–205) or strong (335–341) MHC binding determinant of MalE did not modify the proliferative response to the remaining T cell determinants as compared with wild-type MalE protein. Altogether, these results show that peptide competition for MHC binding may not represent the most important event in processes leading to immunodominance.
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Vijayasimha, Kartikeya, Amy Leigh Leestemaker-Palmer, James Gibb, Jonathan W. Yewdell i Brian P. Dolan. "Targeted protein degradation via NEDD8 conjugation does not enhance direct MHC class I antigen presentation." Journal of Immunology 206, nr 1_Supplement (1.05.2021): 93.01. http://dx.doi.org/10.4049/jimmunol.206.supp.93.01.
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Abstract Knowledge of different pathways contributing to peptide generation for direct MHC class I antigen presentation is important to the field of immunotherapy. Here we investigated the role of the ubiquitin-like protein NEDD8 in antigen presentation. We show that proteins tagged N-terminally with NEDD8 undergo rapid degradation via the proteasomal, and autophagy-lysosomal pathways. To determine if protein NEDDylation increased peptide presentation, we fused NEDD8 to the N-terminus of a cytosolic form of ovalbumin (OVA) and measured presentation of the SIINFEKL peptide via the murine MHC class I molecule K b , and compared the results to ovalbumin N-terminally modified with ubiquitin. While NEDD8-OVA was processed for degradation via the proteasomal and autophagosomal pathway Ub-OVA was only degraded via the proteasome. Peptide presentation from NEDD8-OVA was dependent on NEDD8-ultimate buster 1 (NUB1), while autophagy did not contribute peptides antigen presentation. Overall, we found that N-terminal Ub conjugation was far more effective at generating antigenic peptides than N-terminal NEDD8 conjugation. However, upon inhibition of NEDDYylation by treatment with MLN4924, we did detect a decrease in peptide presentation from a model antigen used specifically to track Defective Ribosomal Product (DRiP) presentation. These data demonstrate that while NEDD8 can cause the rapid degradation of substrates it is not as efficient as Ubiquitin for generating antigenic peptides. Our data provides a basis for understanding the role of NEDD8 in protein degradation and antigen presentation, especially in conditions of NEDD8 dysregulation, such as in some cancers and protein folding pathologies.
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Bacik, I., J. H. Cox, R. Anderson, J. W. Yewdell i J. R. Bennink. "TAP (transporter associated with antigen processing)-independent presentation of endogenously synthesized peptides is enhanced by endoplasmic reticulum insertion sequences located at the amino- but not carboxyl-terminus of the peptide." Journal of Immunology 152, nr 2 (15.01.1994): 381–87. http://dx.doi.org/10.4049/jimmunol.152.2.381.
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Abstract Under most circumstances, cell surface MHC class I molecules display peptides derived from a cytosolic pool of proteins. The efficient presentation of such peptides requires the functioning of two MHC gene products [TAP1 and TAP2 (transporter-associated with Ag processing 1 and 2)] that form a complex that facilitates transmembrane movement of peptides from the cytosol to the endoplasmic reticulum, the site of peptide association with class I molecules. It has been previously shown that peptides can be presented in a TAP-independent manner in association with HLA A2.1 or H-2 Kd if they are expressed COOH-terminal to an endoplasmic reticulum insertion/signal sequence derived from the adenovirus E3/19K glycoprotein (Anderson et al., 1991. J. Exp. Med. 174: 489; Eisenlohr et al., 1992. Cell 71: 963). We show that: 1) the E3/19K signal sequence greatly enhances the presentation of each of four additional peptides tested in association with H-2 Kb or Kk, 2) the E3/19K signal sequence can be substituted by a signal sequence derived from beta-IFN, and 3) the E3/19K signal sequence does not function when located at the COOH terminus of antigenic peptides. These findings indicate that first, many peptides require TAP for efficient presentation to T cells, second, expression of peptides COOH-terminal to signal sequences is a generally applicable method of bypassing the TAP-dependence of peptide presentation and third, the leader sequence does not act to bypass TAP simply by increasing the hydrophobic nature of peptides.
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Zajonc, Dirk M. "Unconventional Peptide Presentation by Classical MHC Class I and Implications for T and NK Cell Activation". International Journal of Molecular Sciences 21, nr 20 (13.10.2020): 7561. http://dx.doi.org/10.3390/ijms21207561.
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T cell-mediated immune recognition of peptides is initiated upon binding of the antigen receptor on T cells (TCR) to the peptide-MHC complex. TCRs are typically restricted by a particular MHC allele, while polymorphism within the MHC molecule can affect the spectrum of peptides that are bound and presented to the TCR. Classical MHC Class I molecules have a confined binding groove that restricts the length of the presented peptides to typically 8–11 amino acids. Both N- and C-termini of the peptide are bound within binding pockets, allowing the TCR to dock in a diagonal orientation above the MHC-peptide complex. Longer peptides have been observed to bind either in a bulged or zig-zag orientation within the binding groove. More recently, unconventional peptide presentation has been reported for different MHC I molecules. Here, either N- or C-terminal amino acid additions to conventionally presented peptides induced a structural change either within the MHC I molecule that opened the confined binding groove or within the peptide itself, allowing the peptide ends to protrude into the solvent. Since both TCRs on T cells and killer immunoglobulin receptors on Natural Killer (NK) cells contact the MHC I molecule above or at the periphery of the peptide binding groove, unconventionally presented peptides could modulate both T cell and NK cell responses. We will highlight recent advances in our understanding of the functional consequences of unconventional peptide presentation in cellular immunity.
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Rimer, Jamie, i Emil Unanue. "Presentation of citrullinated peptides by class II histocompatibility molecules is associated with autophagy. (100.19)". Journal of Immunology 186, nr 1_Supplement (1.04.2011): 100.19. http://dx.doi.org/10.4049/jimmunol.186.supp.100.19.
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Abstract Autoimmune responses to citrullinated proteins are associated with rheumatoid arthritis; however, little is known of the mechanism of citrullination by the antigen presenting cells (APC) of the immune system. Using T cell hybridomas as probes, we found constitutive presentation by class II-Major Histocompatibility Complex (MHC) molecules of a dominant citrullinated peptide from hen egg-white lysozyme (HEL) by either macrophages or dendritic cells. Treatment of APC with 3-Methyladenine (3MA) blocked presentation of the citrullinated peptides after processing unmodified HEL, but presentation of unmodified peptides was not at all affected. In contrast presentation of citrullinated peptides by splenic B cells or B lymphoma cells was not detected under normal culture conditions. However, B cell lines presented citrullinated peptides after serum starvation in a process affected by 3MA treatment or by reducing the expression of the autophagy protein Atg5. Higher levels of citrulline in naturally processed peptides from serum starved B cell lines were detected biochemically. Primary B cells presented citrullinated HEL peptides after engagement of their B cell receptor by antigen or by using anti-immunoglobulin antibodies. Our findings demonstrate a role for autophagy in citrullination of antigen during processing by APC and indicate a link in B cells between engagement of their antigen receptor and presentation of citrullinated peptides.
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Fox, Robert I., i Ho-Il Kang. "Mechanism of Action of Antimalarial Drugs: Inhibition of Antigen Processing and Presentation". Lupus 2, nr 1_suppl (luty 1993): 9–12. http://dx.doi.org/10.1177/0961203393002001031.
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Recent studies have elucidated the steps involved in the association of antigenic peptides with major histocompatibility complex (MHC) encoded proteins and have suggested how antimalarial compounds might influence this important site of immune activation. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome; (b) the synthesis of MHC class II (i.e. HLA-D associated) α, β, and invariant (Ii) chains in the endoplasmic reticulum; (c) the initial association of α-Ii and β-li chains in the endoplasmic reticulum and the transport of these complexes to the primary endosome; (d) the fusion of lysosomal vacuoles and endosomal vacuoles, allowing the mixtures of lysosomal enzymes, peptides, α–Ii and β–Ii; (e) the displacement of Ii chains by peptides to form α–β–peptide complexes in the endosome; and (f) the migration of α–β–peptide complexes to the macrophage cell surface where they can stimulate CD4 T cells, resulting in release of cytokines. A low pH is required for digestion of the protein by acidic hydrolases in the lysosome, for assembly of the α–β–peptide complex and for its transport to the cell surface. Chloroquine and hydroxychloroquine are weak diprotic bases that can diffuse across the cell membrane and raise the pH within cell vesicles. This background provides the underlying basis for the theory that antimalarials may act to prevent autoimmunity by the following putative mechanism. Antimalarial compounds may: (a) stabilize the α-Ii and β-Ii interactions and prevent low-affinity peptides from forming α–β–peptide complexes; and (b) interfere with the efficient movement of α-Ii, β-Ii and α–β–peptide complexes to the correct locations within the cell cytoplasm or to the cell surfaces. Decreased presentation of autoantigenic peptides by macrophages might then lead to downregulation of autoimmune CD4+ T cells and diminish release of cytokines associated with clinical and laboratory signs of autoimmune disease.
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Cram, Erik D., Ryan S. Simmons, Amy L. Palmer, William H. Hildebrand, Daniel D. Rockey i Brian P. Dolan. "Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection". Infection and Immunity 84, nr 2 (23.11.2015): 480–90. http://dx.doi.org/10.1128/iai.01254-15.
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The direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8+cytotoxic T lymphocytes.Chlamydiaspp. are obligate intracellular bacteria and, as such, should be targeted by CD8+T cells. It is likely thatChlamydiaspp. have evolved mechanisms to avoid the CD8+killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of variousChlamydiaspecies to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model-protein-derived peptides. Enhanced self-peptide presentation was detected only when presentation was restricted todefectiveribosomalproducts, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest thatChlamydiaspp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins.
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Shawar, S. M., J. M. Vyas, E. Shen, J. R. Rodgers i R. R. Rich. "Differential amino-terminal anchors for peptide binding to H-2M3a or H-2Kb and H-2Db." Journal of Immunology 151, nr 1 (1.07.1993): 201–10. http://dx.doi.org/10.4049/jimmunol.151.1.201.
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Abstract We previously established that H-2M3a, the H chain of the maternally transmitted Ag (Mta), is specialized for presentation of N-formylated peptides. We hypothesized that the N-formyl group might prevent or limit the presentation of peptide Ag by H-2K and H-2D molecules. We now show by Mta- and OVA-specific CTL assays, peptide competition, and immunofluorescence analyses that N-formyl modification of four antigenic peptides inhibited their binding by either H-2Kb (OVAMet258-264, VSVNP52-59, and SVNP324-332) or H2-Db (SVNP324-332, and IVNP366-374). In contrast, N-formyl-OVAMet258-264 did bind to H2-M3a. The data imply lack of an N-formyl-binding pocket in classical MHC class I molecules and are consistent with a specialized role for H2-M3a in presentation of N-formylated peptides such as derived from intracellular prokaryotic parasites.
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van Ham, Marieke, Marcel van Lith, Björn Lillemeier, Esther Tjin, Ulrike Grüneberg, Dinah Rahman, Liesbeth Pastoors i in. "Modulation of the Major Histocompatibility Complex Class II–Associated Peptide Repertoire by Human Histocompatibility Leukocyte Antigen (Hla)-Do". Journal of Experimental Medicine 191, nr 7 (27.03.2000): 1127–36. http://dx.doi.org/10.1084/jem.191.7.1127.
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Antigen presentation by major histocompatibility complex class II molecules is essential for antibody production and T cell activation. For most class II alleles, peptide binding depends on the catalytic action of human histocompatibility leukocyte antigens (HLA)-DM. HLA-DO is selectively expressed in B cells and impedes the activity of DM, yet its physiological role remains unclear. Cell surface iodination assays and mass spectrometry of major histocompatibility complex class II–eluted peptides show that DO affects the antigenic peptide repertoire of class II. DO generates both quantitative and qualitative differences, and inhibits presentation of large-sized peptides. DO function was investigated under various pH conditions in in vitro peptide exchange assays and in antigen presentation assays using DO− and DO+ transfectant cell lines as antigen-presenting cells, in which effective acidification of the endocytic pathway was prevented with bafilomycin A1, an inhibitor of vacuolar ATPases. DO effectively inhibits antigen presentation of peptides that are loaded onto class II in endosomal compartments that are not very acidic. Thus, DO appears to be a unique, cell type–specific modulator mastering the class II–mediated immune response induced by B cells. DO may serve to increase the threshold for nonspecific B cell activation, restricting class II–peptide binding to late endosomal compartments, thereby affecting the peptide repertoire.
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Legge, Kevin L., Booki Min, Nicholas T. Potter i Habib Zaghouani. "Presentation of a T Cell Receptor Antagonist Peptide by Immunoglobulins Ablates Activation of T Cells by a Synthetic Peptide or Proteins Requiring Endocytic Processing". Journal of Experimental Medicine 185, nr 6 (17.03.1997): 1043–54. http://dx.doi.org/10.1084/jem.185.6.1043.
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T cell receptor (TCR) antagonism is being considered for inactivation of aggressive T cells and reversal of T cell–mediated autoimmune diseases. TCR antagonist peptides silence aggressive T cells and reverse experimental allergic encephalomyelitis induced with free peptides. However, it is not clear whether free antagonist peptides could reverse natural disease where the antigen is presumably available for endocytic processing and peptides gain access to newly synthesized class II MHC molecules. Using an efficient endocytic presentation system, we demonstrate that a proteolipid protein (PLP) TCR antagonist peptide (PLP-LR) presented on an Ig molecule (IgPLP-LR) abrogates the activation of T cells stimulated with free encephalitogenic PLP peptide (PLP1), native PLP, or an Ig containing PLP1 peptide (Ig-PLP1). Free PLP-LR abolishes T cell activation when the stimulator is free PLP1 peptide, but has no measurable effect when the stimulator is the native PLP or Ig-PLP1. In vivo, Ig-PLP1 induces a T cell response to PLP1 peptide. However, when coadministered with Ig-PLP-LR, the response to PLP1 peptide is markedly reduced whereas the response to PLP-LR is normal. Free PLP-LR coadministered with Ig-PLP1 has no effect on the T cell response to PLP1. These findings indicate that endocytic presentation of an antagonist peptide by Ig outcompete both external and endocytic agonist peptides whereas free antagonist hinders external but not endocytic agonist peptide. Direct contact with antagonist ligand and/or trans-regulation by PLP-LR–specific T cells may be the operative mechanism for Ig-PLP-LR–mediated downregulation of PLP1-specific T cells in vivo. Efficient endocytic presentation of antagonist peptides, which is the fundamental event for either mechanism, may be critical for reversal of spontaneous T cell–mediated autoimmune diseases where incessant endocytic antigen processing could be responsible for T cell aggressivity.
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Sorvillo, Nicoletta, Simon D. van Haren, Paul H. Kaijen, Anja ten Brinke, Rob Fijnheer, Alexander B. Meijer i Jan Voorberg. "Preferential HLA-DRB1*11 Dependent Presentation of CUB2 Derived Peptides by ADAMTS13 Pulsed Dendritic Cells". Blood 120, nr 21 (16.11.2012): 489. http://dx.doi.org/10.1182/blood.v120.21.489.489.
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Abstract Abstract 489 Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). Recently, HLA-DRB1*11 has been identified as a risk factor for the development of acquired TTP. Here, we identified ADAMTS13-derived peptides presented on MHC class II alleles. Dendritic cells from a panel of both HLA-DRB1*11 positive and negative donors were pulsed with ADAMTS13 and the HLA-DR-presented peptide repertoire was analyzed by mass spectrometry. Interestingly, pulsing of dendritic cells of HLA-DRB1*11 positive donors with 100 nM ADAMTS13 resulted in presentation of a single CUB2 derived ADAMTS13 peptide. This peptide was not presented by HLA-DRB1*11 negative donors. Pulsing of HLA-DRB1*0301 positive cells with 100 nM ADAMTS13 resulted in presentation of a different CUB2 domain derived peptide in 2 out of 3 donors analyzed. Pulsing of dendritic cells employing higher concentrations of ADAMTS13 (500 nM) resulted in increased presentation of ADAMTS13 derived peptides by both HLA-DRB1*11 positive and negative donors. In DRB1*11 negative donors peptides derived of multiple domains were presented which included spacer, TSR2-8, metalloprotease and disintegrin domains. Interestingly, the CUB2 domain peptide (specific for DRB1*11 when dendritic cells were pulsed with 100 nM ADAMTS13) was also presented under these conditions. Apparently, this peptide can be presented by multiple MHC class II alleles although higher concentrations of ADAMTS13 are required for its presentation on DCs derived of non-DRB1*11 positive donors. Interestingly, the diversity of ADAMTS13 derived peptides presented by iDCs of donors HLA-DRB1*11 was not affected by pulsing of iDCs with higher concentration of ADAMTS13. Also, under these conditions the only peptides that were presented were derivatives of the CUB2 domain derived peptide that was also presented at lower concentrations of ADAMTS13. Our results clearly demonstrate that this peptide is efficiently presented when compared to other ADAMTS13-derived peptides. Therefore, we hypothesize that efficient presentation of this CUB2 domain derived peptide on DRB1*11 may provoke proliferation of low affinity self-reactive CD4+ T cells that have escaped negative selection in the thymus and contribute to the onset of acquired TTP. Together these findings may provide further insight in the initiation of the autoimmune reactivity against ADAMTS13 in patients affected by TTP. Disclosures: No relevant conflicts of interest to declare.
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Chen, B. P., A. Madrigal i P. Parham. "Cytotoxic T cell recognition of an endogenous class I HLA peptide presented by a class II HLA molecule." Journal of Experimental Medicine 172, nr 3 (1.09.1990): 779–88. http://dx.doi.org/10.1084/jem.172.3.779.
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Human leukocytes were stimulated in vitro with peptides corresponding in sequence to the highly variable helix of the alpha 1 domain of various HLA-B and -C molecules. A CD4+ CD8- cytotoxic T cell line, CTL-AV, that is specific for the HLA-B7 peptide presented by HLA-DR11.1 was obtained. The HLA-DR11.2 molecule, which only differs at three residues from HLA-DR11.1, did not present the HLA-B7 peptide to CTL-AV. Peptides from the alpha 1 domain helix of other HLA-A and HLA-B molecules, but not HLA-C molecules, competed with the HLA-B7 peptide for binding to HLA-DR11.1. A cell line (WT50) that coexpresses HLA-B7 and HLA-DR11.1 was killed by CTL-AV in the absence of any added HLA-B7 peptide. The processing and presentation of HLA-B7 in these cells appears to be through the endogenous, and not the exogenous, pathway of antigen presentation. Thus, Brefeldin A inhibits presentation and chloroquine does not. Furthermore, introduction of purified HLA-B7 molecules into HLA-DR11.1+, HLA-B7- cells by cytoplasmic loading via osmotic lysis of pinosomes, but not by simple incubation, rendered them susceptible to CTL-AV killing. These results provide an example of class II major histocompatibility complex (MHC) presentation of a constitutively synthesized self protein that uses the endogenous pathway of antigen presentation. They also emphasize the capacity for presentation of MHC peptides by MHC molecules.
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Garg, Manish, Margaret K. Callahan i Pramod K. Srivastava. "Essential role of heat shock protein 90 in direct and cross-presentation (93.13)". Journal of Immunology 178, nr 1_Supplement (1.04.2007): S168. http://dx.doi.org/10.4049/jimmunol.178.supp.93.13.
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Abstract Direct antigen presentation involves the generation of peptides by proteasomes, ferrying of peptides from cytosol to endoplasmic reticulum and finally, formation and transport of peptide-MHC I complexes. Chaperones hsp90, hsp70, gp96 and TriC have previously been shown to associate with MHC class I epitopes and their precursors. Here, we have treated cells with hsp90 inhibitors Radicicol, 17-AAG or geldanamycin and observe that (i) treatment of cells with such inhibitors leads, in a dose-and time- dependent fashion, to a decrease in the levels of peptide-bound but not total cell surface MHC I; (ii) Radicicol does not affect transport of non-MHC I, control proteins to the cell surface; (iii) Radicicol does not impair MHC I synthesis; and (iv) the reduction in surface MHC I expression caused by Radicicol, is restored by pulsing cells with exogenous peptides. These results indicate an essential role for hsp90 in peptide-transport during endogenous (direct) presentation. During indirect or cross-presentation, antigen presenting cells acquire, process and present exogenous antigen onto the MHC I. Our previous studies (Binder and Srivastava, 2005, Nature Immunology 6, 593) have shown an essential role for HSP-chaperoned peptides in this process. In that study, cell lysates replete with or depleted of one or several HSP-peptide complexes were used to study cross-priming. We have now examined cross-priming by intact cells instead of cell lysates and we observe that hsp90 plays a unique, essential and non-redundant role in cross-priming as well. Data that bear on the mechanism of post-proteasomal transport of peptides, shall be presented.
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Ma, Yue, i Yoko Yamakoshi. "(Invited, Digital Presentation) Aggregation Switchable Fullerene-Peptides Conjugates". ECS Meeting Abstracts MA2022-01, nr 11 (7.07.2022): 810. http://dx.doi.org/10.1149/ma2022-0111810mtgabs.
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Intensive research has been applied on chemical functionalization of fullerenes over the past decades, aiming at utilizing their broad availabilities in chemical biology field. Chemical moieties was induced to improve their water solubility and thus enhance their properties or interaction with biomolecules. In our previous study, we reported the synthesis of fullerene-PEG conjugates and demonstrated their ability for photoinduced DNA damage and ROS generation under visible light irradiation. In this work, we report a water-soluble fullerene derivative by constructing a fullerene-peptide conjugates. The aggregation behavior as well as bio properties has been systematically studied for this series of fullerene-peptide conjugates (Figure 1a). By altering the attached peptides, fullerenes could exist as monomer or micelle in aqueous phase (Figure 1b). Figure 1
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Nagamine, Brandy S., i Brian P. Dolan. "The unfolded protein response alters MHC class I antigen presentation in a mouse cell line". Journal of Immunology 200, nr 1_Supplement (1.05.2018): 99.9. http://dx.doi.org/10.4049/jimmunol.200.supp.99.9.
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Abstract Direct MHC class I antigen presentation is a necessary step to identify cells for elimination by cytotoxic CD8+ T cells. Antigenic peptides may originate from host-derived unnecessary or “retired” proteins as well as defective ribosomal products (DRiPs). DRiPs are newly synthesized polypeptides incapable of attaining a stable configuration and are thus rapidly degraded. The balance between protein synthesis and degradation, key processes to antigenic peptide generation, are likely influenced by the unfolded protein response (UPR). The UPR is a cellular response designed to alleviate the toxic accumulation of unfolded proteins in the endoplasmic reticulum. Several disease conditions requiring CD8+ T cell responses such as viral infection and tumorigenesis are known to influence the UPR. In this study, we utilized small inhibitory molecules targeting individual branches of the UPR to investigate the effect on both global MHC class I levels and the presentation of peptides from both DRiP and non-DRiP sources. Inhibition of the IRE1α signaling pathway but not the PERK pathway reduced total MHC class I levels. Presentation of peptides derived from DRiPs was unaffected by inhibiting either branch of the UPR. These data suggest that specific perturbations to the UPR has the capacity to alter host antigen presentation of peptides from particular peptide sources.
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Hall, Pamela R., Brian Hjelle, David C. Brown, Chunyan Ye, Virginie Bondu-Hawkins, Kathleen A. Kilpatrick i Richard S. Larson. "Multivalent Presentation of Antihantavirus Peptides on Nanoparticles Enhances Infection Blockade". Antimicrobial Agents and Chemotherapy 52, nr 6 (7.04.2008): 2079–88. http://dx.doi.org/10.1128/aac.01415-07.
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ABSTRACT Viral entry into susceptible host cells typically results from multivalent interactions between viral surface proteins and host entry receptors. In the case of Sin Nombre virus (SNV), a New World hantavirus that causes hantavirus cardiopulmonary syndrome, infection involves the interaction between viral membrane surface glycoproteins and the human integrin αvβ3. Currently, there are no therapeutic agents available which specifically target SNV. To address this problem, we used phage display selection of cyclic nonapeptides to identify peptides that bound SNV and specifically prevented SNV infection in vitro. We synthesized cyclic nonapeptides based on peptide sequences of phage demonstrating the strongest inhibition of infection, and in all cases, the isolated peptides were less effective at blocking infection (9.0% to 27.6% inhibition) than were the same peptides presented by phage (74.0% to 82.6% inhibition). Since peptides presented by the phage were pentavalent, we determined whether the identified peptides would show greater inhibition if presented in a multivalent format. We used carboxyl linkages to conjugate selected cyclic peptides to multivalent nanoparticles and tested infection inhibition. Two of the peptides, CLVRNLAWC and CQATTARNC, showed inhibition that was improved over that of the free format when presented on nanoparticles at a 4:1 nanoparticle-to-virus ratio (9.0% to 32.5% and 27.6% to 37.6%, respectively), with CQATTARNC inhibition surpassing 50% when nanoparticles were used at a 20:1 ratio versus virus. These data illustrate that multivalent inhibitors may disrupt polyvalent protein-protein interactions, such as those utilized for viral infection of host cells, and may represent a useful therapeutic approach.
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Lee, Daniel, Andy J. Minn i Lexus R. Johnson. "CAR-T cells to deliver engineered peptide antigens and reprogram antigen specific T cell responses against solid tumors." Journal of Clinical Oncology 39, nr 15_suppl (20.05.2021): 2530. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2530.
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2530 Background: Neoantigen depleted malignancies such as colorectal cancer demonstrate primary resistance to immune checkpoint blockade, and solid tumors in general have shown resistance to chimeric antigen receptor (CAR) T cell therapy. However, CAR-T cells have been shown to be capable of delivering various therapeutic molecules in a targeted fashion to the tumor microenvironment, in some cases through extracellular vesicles (EVs). In vivo studies have shown that the presentation of foreign viral peptides by solid tumors can reprogram bystander virus-specific cytotoxic T cells (CTLs) against tumor cells. In this study, we demonstrate that CAR-T cells can deliver engineered peptide antigens to solid tumors, leading to presentation on tumor cells and anti-tumor response. Methods: Second generation CAR-T cells (41BB endodomain) targeting human CD19 (19BBz) or human mesothelin (M5BBz) were generated via retroviral and lentiviral transduction respectively. CAR-T cells were engineered to co-express peptides such as SIINFEKL of ovalbumin and NLVPMVATV of CMV pp65 among others. Peptides were isolated from EVs via ultracentrifugation. For in vivo studies, C57BL/6 or NSG mice were injected on the flank with relevant tumors and treated with peptide-CAR-T cells. In vitro studies utilized flow cytometry and xCELLigence killing assays. Results: Murine 19BBz CAR-T cells expressing the SIINFEKL peptide of ovalbumin (ova-19BBz) were found to transfer SIINFEKL peptide to tumor cells via EVs in vitro and in vivo, leading to peptide presentation on MHC-I of tumor cells. This resulted in significantly delayed tumor growth in tumor bearing mice transfused with OT-I T cells to mimic an existing antigen specific T cell pool. We expanded on these findings by isolating EVs from human M5BBz CAR-T cells expressing CMV viral peptides. Peptide-CAR-T EVs were co-cultured with human ovarian cancer cells to assess presentation to Jurkat T cells. Finally, we utilized primary human T cells from CMV+ healthy donors to assess the clinical feasibility of our peptide delivery approach. Conclusions: CAR-T cells can be engineered to deliver peptides to tumor cells for presentation and subsequent targeting by antigen specific CTLs. This represents a novel strategy for the treatment of non-immunogenic tumors.
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Rosloniec, E. F., L. J. Vitez, S. Buus i J. H. Freed. "MHC class II-derived peptides can bind to class II molecules, including self molecules, and prevent antigen presentation." Journal of Experimental Medicine 171, nr 5 (1.05.1990): 1419–30. http://dx.doi.org/10.1084/jem.171.5.1419.
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Seven synthetic peptides corresponding to the polymorphic regions of the alpha and beta chains of the I-Ak molecule were examined for their ability to inhibit the presentation of foreign antigens to antigen-specific, I-A-restricted T cell hybridomas. Two of the peptides, representing the sequences found in the first and third polymorphic regions (PMR) of the A alpha k chain (alpha k-1 and alpha k-3) were capable of inhibiting the presentation of three different HEL-derived peptide antigens to their appropriate T cells. In addition, the alpha k-1 peptide inhibited the presentation of the OVA(323-339) immunodominant peptide to the I-Ad-restricted T cell hybridomas specific for it. Prepulsing experiments demonstrated that the PMR peptides were interacting with the APC and not with the T cell hybridomas. These observations were confirmed and extended by the demonstration that the alpha k-1 and alpha k-3 peptides blocked the direct binding of HEL(46-61) to purified I-Ak and that the alpha k-1 peptide blocked the binding of OVA(323-339) to I-Ad. The binding competition experiments suggest that the alpha k-1 peptide binds to the I-Ak molecule from which it was derived with a Kd approximately 10(-5) M, while the alpha k-3 peptide binds slightly less well. These combined data, suggesting that class II-derived peptides can bind to MHC class II molecules, including the autologous molecule from which they are derived, have important implications for the molecular basis of alloreactivity and autoreactivity. Further, they suggest a possible mechanism by which selecting elements, involving only MHC molecules, may be generated in the thymus.
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Dörfel, Daniela, Silke Appel, Frank Grünebach, Markus M. Weck, Martin R. Müller, Annkristin Heine i Peter Brossart. "Processing and presentation of HLA class I and II epitopes by dendritic cells after transfection with in vitro–transcribed MUC1 RNA". Blood 105, nr 8 (15.04.2005): 3199–205. http://dx.doi.org/10.1182/blood-2004-09-3556.
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AbstractRNA transfection of dendritic cells (DCs) was shown to be highly efficient in eliciting CD8+ and CD4+ T-cell responses. However, antigen presentation pathways involved in generation of human leukocyte antigen (HLA) class I and class II peptides have remained elusive. To analyze this we incubated mucin 1 (MUC1) RNA-transfected DCs with compounds known to inhibit HLA class I presentation and used these cells in chromium 51 (51Cr)–release assays. As effectors, we used cytotoxic T lymphocyte (CTL) lines specific for the MUC1 peptides M1.1 and M1.2. We observed that the presentation of HLA-A*02 epitopes is inhibited by brefeldin A and lactacystin. To determine the requirement of a functional transporter associated with antigen processing (TAP), we cotransfected DCs with MUC1 and infected cell peptide 47 (ICP47) RNA. ICP47 could only inhibit the presentation of the M1.1 but not the M1.2 peptide, indicating that this epitope derived from the signal sequence is presented independently of TAP. Cocultivation of MUC1 RNA-transfected DCs with MUC1-specific CD4+ T lymphocytes revealed that the presentation of HLA class II peptides is sensitive to proteasomal inhibitors and brefeldin A. Furthermore, the presentation pathway requires lysosomal and endosomal processing and is mediated by autophagy. Our results demonstrate that the efficient presentation of cytosolic proteins on major histocompatibility complex (MHC) class II combines the proteolytic and lysosomal pathways.
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Mellins, E., P. Cameron, M. Amaya, S. Goodman, D. Pious, L. Smith i B. Arp. "A mutant human histocompatibility leukocyte antigen DR molecule associated with invariant chain peptides." Journal of Experimental Medicine 179, nr 2 (1.02.1994): 541–49. http://dx.doi.org/10.1084/jem.179.2.541.
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From a human histocompatibility leukocyte antigen (HLA)-DR/DQ hemizygous, B lymphoblastoid progenitor, we isolated a cell line, 10.24.6, with a DR alpha missense mutation (96P-->96S), which results in an N-linked carbohydrate addition at position 94 in the DR alpha 2 domain. Several features of 10.24.6 cells suggest that the mutation disrupts normal intracellular formation of peptide/DR complexes. The mutant HLA-DR dimers, though expressed at the cell surface, lack the conformation of the mature, peptide-loaded class II molecules of the progenitor cell, as assessed by their loss of binding of certain antibodies and by the lack of stability in detergent (sodium dodecyl sulfate) solution. In addition, presentation of endocytosed antigen to HLA-DR-restricted T cells is defective in the mutant, but can be restored by transfection of a wild type DRA gene. Assays with synthetic peptides indicate that the 10.24.6 phenotype is not due to an intrinsic inability of the mutant DR molecules to bind peptides. Therefore, to directly evaluate peptide occupancy of the mutant molecules, we analyzed acid-eluted, HLA-DR-associated peptides. The predominant species from the 10.24.6 mutant is a nested set of invariant chain (Ii)-derived peptides that are undetectable in the DR eluate from progenitor cells. The region of DR alpha altered in the mutant molecules is thus implicated in normal formation of peptide/DR complexes. Further, the same set of Ii peptides associated with the DR molecules is present in the eluate from an antigen presentation mutant with a defect in an major histocompatibility complex (MHC)-linked gene. These results suggest that DR molecules in 10.24.6 and in certain presentation mutants are affected at the same or related steps in class II molecule biosynthesis, raising the possibility that class II molecules interact with an MHC-encoded accessory molecule during antigen presentation.
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Adorini, L., J. Moreno, F. Momburg, G. J. Hämmerling, J. C. Guéry, A. Valli i S. Fuchs. "Exogenous peptides compete for the presentation of endogenous antigens to major histocompatibility complex class II-restricted T cells." Journal of Experimental Medicine 174, nr 4 (1.10.1991): 945–48. http://dx.doi.org/10.1084/jem.174.4.945.
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Antigen-presenting cells (APC) transfected with a construct encoding the hen egg-white lysozyme (HEL) amino acid sequence 1-80 constitutively present HEL peptides complexed to major histocompatibility complex (MHC) class II molecules to specific T cell hybridomas, indicating that endogenous cellular antigens can be efficiently presented to class II-restricted T cells. Here we show that exogenous peptide competitors added to HEL-transfected APC can inhibit the presentation of endogenous HEL peptides to class II-restricted T cells. The inhibition is specific for the class II molecule binding the competitor peptide, and it affects to the same extent presentation of exogenous or endogenous HEL peptides. These results, demonstrating that an exogenous competitor can inhibit class II-restricted T cell activation induced by endogenous as well as exogenous antigen, suggest lack of strict compartmentalization between endogenous and exogenous pathways of antigen presentation. Since autoreactive T cells may recognize endogenous, as well as exogenous antigens, the results have implications for the treatment of autoimmune diseases by MHC blockade.
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Haque, Syed Mahdee, Abdul-Rahman Salman, Hamdi Abdeen, Elizabeth Krieger, Masoud Manjili, Rehan Qayyum, Sosipatros Alexandros Boikos i Amir A. Toor. "Cancer immunotherapy: Identifying cancer testis antigen peptides to enhance antitumor response." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): e20022-e20022. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e20022.
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e20022 Background: Cancer testis antigens (CTAs) are highly immunogenic, tissue-restricted proteins that may be over expressed in hematological malignancies. In this study, an in silico analysis of CTA-derived peptide presentation on HLA class I molecules is reported with an aim to identify putative CTA peptides with a high estimated binding affinity to known HLA class I molecules. Methods: Eighty unique HLA Class I alleles (HLA-A, B, and C), across 78 hematopoietic cell transplant recipients were computationally studied for their ability to bind peptides derived from three CTAs. The amino acid sequences of all three CTA proteins were obtained from UniProtKB. NetMHCPan-4.1 was utilized for in silico prediction of HLA class I binding affinities of the 9-mer peptides generated from these CTAs. Results: The CTA MAGE-A1 had 1202 unique peptides predicted to bind at least one HLA class I allele and 176 of these peptides were classified as strong binders (Rank <0.5 and IC50<500nM). Conversely, 71 unique HLA class 1 alleles were predicted to bind strongly to at least one MAGE-A1 derived peptide. The ability of different MAGE-A1 peptides to bind HLA varied considerably, e.g., peptide TSYVKVLEY, was predicted to bind strongly to 22 different HLA class I alleles. Similarly, 41 CTAG-1B-derived and 164 MAGE-A2-derived peptides were predicted to generate strong binders with at least one HLA class 1 allele. Conversely, 37 and 71 unique HLA class I alleles were predicted to bind strongly to at least one CTAG1B peptide and one MAGE-A1 peptide, respectively. CTAG1-B derived peptide FATPMEAEL and MAGE-A2-derived peptide FAHPRKLLM were predicted to bind strongly to 17 and 22 HLA class 1 alleles, respectively. In aggregate most patients presented multiple peptides across the 6 HLA class I molecules studied (Table). The number of strongly binding MAGE-A1 and CTAG-1B peptides from unique patients. Strong binding defined by Rank <0.5 and IC50<500nM. Conclusions: Most patients presented several CTA derived peptides, suggesting that the aggregate HLA presentation across the 6 classical HLA class I molecules will yield high odds of presentation of CTA expressed by target tissues. These HLA genotype-informed quantitative analyses raise the possibility that agents such as checkpoint inhibitors and immunomodulatory drugs may synergize with hypomethylating agents and augment CTA-directed T-cell responses.[Table: see text]
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Lazarski, Christopher A., Francisco A. Chaves i Andrea J. Sant. "The impact of DM on MHC class II–restricted antigen presentation can be altered by manipulation of MHC–peptide kinetic stability". Journal of Experimental Medicine 203, nr 5 (8.05.2006): 1319–28. http://dx.doi.org/10.1084/jem.20060058.
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DM edits the peptide repertoire presented by major histocompatibility complex class II molecules by professional antigen-presenting cells (APCs), favoring presentation of some peptides over others. Despite considerable research by many laboratories, there is still significant uncertainty regarding the biochemical attributes of class II–peptide complexes that govern their susceptibility to DM editing. Here, using APCs that either do or do not express DM and a set of unrelated antigens, we found that the intrinsic kinetic stability of class II–peptide complexes is tightly correlated with the effects of DM editing within APCs. Furthermore, through the use of kinetic stability variants of three independent peptides, we demonstrate that increasing or decreasing the kinetic stability of class II–peptide complexes causes a corresponding alteration in DM editing. Finally, we show that the spontaneous kinetic stability of class II complexes correlates directly with the efficiency of presentation by DM+ APCs and the immunodominance of that class II–peptide complex during an immune response. Collectively, these results suggest that the pattern of DM editing in APCs can be intentionally changed by modifying class II–peptide interactions, leading to the desired hierarchy of presentation on APCs, thereby promoting recruitment of CD4 T cells specific for the preferred peptides during an immune response.
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Banerjee, Soumya, i S. Jonathan Chapman. "Influence of correlated antigen presentation on T-cell negative selection in the thymus". Journal of The Royal Society Interface 15, nr 148 (listopad 2018): 20180311. http://dx.doi.org/10.1098/rsif.2018.0311.
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The thymus is the primary organ for the generation of naive T cells, a key component of the immune system. Tolerance of T cells to self is achieved primarily in the thymic medulla, where immature T cells (thymocytes) sample self-peptides presented by medullary thymic epithelial cells (mTECs). A sufficiently strong interaction activates the thymocytes leading to negative selection. A key question of current interest is whether there is any structure in the manner in which mTECs present peptides: can any mTEC present any peptide at any time, or are there particular patterns of correlated peptide presentation? We investigate this question using a mathematical model of negative selection. We find that correlated patterns of peptide presentation may be advantageous in negatively selecting low-degeneracy thymocytes (that is, those thymocytes which respond to relatively few peptides). We also quantify the probability that an auto-reactive thymocyte exits the thymus before it encounters a cognate antigen. The results suggest that heterogeneity of gene co-expression in mTECs has an effect on the probability of escape of autoreactive thymocytes.
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van Ham, S. M., U. Grüneberg, G. Malcherek, I. Bröker, A. Melms i J. Trowsdale. "Human histocompatibility leukocyte antigen (HLA)-DM edits peptides presented by HLA-DR according to their ligand binding motifs." Journal of Experimental Medicine 184, nr 5 (1.11.1996): 2019–24. http://dx.doi.org/10.1084/jem.184.5.2019.
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Human histocompatibility leukocyte antigen (HLA)-DM is a facilitator of antigen presentation via major histocompatibility complex (MHC) class II molecules. In the absence of HLA-DM, MHC class II molecules do not present natural peptides, but tend to remain associated with class II-associated invariant chain peptides (CLIP). Recently, DM was shown to catalyze the release of CLIP from HLA-DR. We have investigated which peptides bound to HLA-DR are vulnerable to release upon encountering DM. By directed substitution of allele-specific anchor residues between CLIP and DR3-cognate peptides and the application of recombinant DM we show that DM catalyzes the release of those peptides bound to HLA-DR3 that do not have appropriate anchor residues and, hence, no optimal ligand binding motif. Thus, HLA-DM acts as a peptide editor, facilitating selection of peptides that stably bind to class II molecules for eventual presentation to the immune system from the pool of available peptides.
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Rucevic, Marijana, Georgio Kourjian, Julie Boucau, Renata Blatnik, Wilfredo Garcia Bertran, Matthew J. Berberich, Bruce D. Walker, Angelika B. Riemer i Sylvie Le Gall. "Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses". Journal of Virology 90, nr 19 (20.07.2016): 8605–20. http://dx.doi.org/10.1128/jvi.00599-16.
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ABSTRACTDespite the critical role of epitope presentation for immune recognition, we still lack a comprehensive definition of HIV peptides presented by HIV-infected cells. Here we identified 107 major histocompatibility complex (MHC)-bound HIV peptides directly from the surface of live HIV-transfected 293T cells, HIV-infected B cells, and primary CD4 T cells expressing a variety of HLAs. The majority of peptides were 8 to 12 amino acids (aa) long and mostly derived from Gag and Pol. The analysis of the total MHC-peptidome and of HLA-A02-bound peptides identified new noncanonical HIV peptides of up to 16 aa that could not be predicted by HLA anchor scanning and revealed an heterogeneous surface peptidome. Nested sets of surface HIV peptides included optimal and extended HIV epitopes and peptides partly overlapping or distinct from known epitopes, revealing new immune responses in HIV-infected persons. Surprisingly, in all three cell types, a majority of Gag peptides derived from p15 rather than from the most immunogenic p24. The cytosolic degradation of peptide precursors in corresponding cells confirmed the generation of identified surface-nested peptides. Cytosolic degradation revealed peptides commonly produced in all cell types and displayed by various HLAs, peptides commonly produced in all cell types and selectively displayed by specific HLAs, and peptides produced in only one cell type. Importantly, we identified areas of proteins leading to common presentations of noncanonical peptides by several cell types with distinct HLAs. These peptides may benefit the design of immunogens, focusing T cell responses on relevant markers of HIV infection in the context of HLA diversity.IMPORTANCEThe recognition of HIV-infected cells by immune T cells relies on the presentation of HIV-derived peptides by diverse HLA molecules at the surface of cells. The landscape of HIV peptides displayed by HIV-infected cells is not well defined. Considering the diversity of HLA molecules in the human population, it is critical for vaccine design to identify HIV peptides that may be displayed despite the HLA diversity. We identified 107 HIV peptides directly from the surface of three cell types infected with HIV. They corresponded to nested sets of HIV peptides of canonical and novel noncanonical lengths not predictable by the presence of HLA anchors. Importantly, we identified areas of HIV proteins leading to presentation of noncanonical peptides by several cell types with distinct HLAs. Including such peptides in vaccine immunogen may help to focus immune responses on common markers of HIV infection in the context of HLA diversity.
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Kropp, Laura, Manish Garg i Robert Binder. "Ovalbumin-derived precursor peptides are transferred sequentially from gp96 and calreticulin to MHC I in the endoplasmic reticulum (130.26)". Journal of Immunology 184, nr 1_Supplement (1.04.2010): 130.26. http://dx.doi.org/10.4049/jimmunol.184.supp.130.26.
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Abstract Cellular peptides generated by proteasomal degradation of proteins in the cytosol and destined for presentation by MHC I are associated with several chaperones. Hsp70, hsp90, and the TCP1-ring complex have been implicated as important cytosolic players for chaperoning these peptides. In this study we report that gp96 and calreticulin are essential for chaperoning peptides in the endoplasmic reticulum. Importantly we demonstrate that cellular peptides are transferred sequentially from gp96 to calreticulin and then to MHC I forming a relay line. Disruption of this relay line by removal of gp96 or calreticulin prevents the binding of peptides by MHC I and hence presentation of the MHC 1-peptide complex on the cell surface. Our results are important for understanding how peptides are processed and trafficked within the endoplasmic reticulum before exiting in association with MHC I heavy chains and beta2-microglobulin as a trimolecular complex.
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Zügel, U., B. Schoel i S. H. Kaufmann. "Beta 2-microglobulin independent presentation of exogenously added foreign peptide and endogenous self-epitope by MHC class I alpha-chain to a cross-reactive CD8+ CTL clone." Journal of Immunology 153, nr 9 (1.11.1994): 4070–80. http://dx.doi.org/10.4049/jimmunol.153.9.4070.
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Abstract CD8+ T cells recognize antigenic peptides in the context of MHC class I molecules that encompass two distinct polypeptide chains, the MHC-encoded alpha-chain and the non-MHC-encoded beta 2-microglobulin (beta 2-m). The beta 2-m is considered essential for the stability and function of the MHC class I peptide complex and, hence, for peptide presentation to CD8+ T cells. In this study, we describe peptide presentation by macrophages from beta 2-m-deficient mice to a CD8+ CTL clone tht cross-recognizes an H-2Db-restricted peptide of the mycobacterial heat shock protein 60 (hsp60) and a self-peptide presented by IFN-gamma-stressed macrophages. Specific lysis of stressed or hsp60 peptide-pulsed beta 2-m-/- macrophages was inhibited by the nucleoprotein peptide with high affinity to H-2Db. Brefeldin A, a known inhibitor of MHC class I processing, interfered with lysis of IFN-gamma-stressed, but not of hsp60 peptide-pulsed, beta 2-m-/- macrophages. The hsp60 peptide failed to stimulate surface expression of H-2Db in beta 2-m-/- macrophages, and slightly increased MHC class I expression in the transporter mutant cell line RMA-S, as detected by cytofluorometry. We concLude that presentation of endogenously processed cytosolic epitopes and exogenously added foreign peptides by the MHC class I alpha-chain can occur independent from beta 2-m. Presumably, H-2Db peptides, but not H-2Kb peptides, have the capacity to induce and/or stabilize surface expression of a small number of MHC class I alpha-chains, and this low density is sufficient for recognition by CD8+ CTL, although it need not be detected by serologic means.