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Immanuel F Luescher - One of the best experts on this subject based on the ideXlab platform.
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Effects of Epitope Modification on T Cell Receptor–Ligand Binding and Antigen Recognition by Seven H-2Kd –restricted Cytotoxic T Lymphocyte Clones Specific for a Photoreactive Peptide Derivative
2013Co-Authors: M. Kessler, Jean-charles Cerottini, Paolo Bassanini, Immanuel F LuescherAbstract:We tested for Antigen Recognition and T cell receptor (TCR)–ligand binding 12 peptide derivative variants on seven H-2K d –restricted cytotoxic T lymphocytes (CTL) clones specific for a bifunctional photoreactive derivative of the Plasmodium berghei circumsporozoite peptide 252– 260 (SYIPSAEKI). The derivative contained iodo-4-azidosalicylic acid in place of PbCS S-252 and 4-azidobenzoic acid on PbCS K-259. Selective photoactivation of the N-terminal photoreactive group allowed crosslinking to K d molecules and photoactivation of the orthogonal group to TCR. TCR photoaffinity labeling with covalent K d –peptide derivative complexes allowed direct assessment of TCR–ligand binding on living CTL. In most cases (over 80%) cytotoxicity (chromium release) and TCR–ligand binding differed by less than fivefold. The exceptions included (a) partial TCR agonists (8 cases), for which Antigen Recognition was fivetenfold less efficient than TCR–ligand binding, (b) TCR antagonists (2 cases), which were not recognized and capable of inhibiting Recognition of the wild-type conjugate, (c) heteroclitic agonists (2 cases), for which Antigen Recognition was more efficient than TCR–ligand binding, and (d) one partial TCR agonist, which activated only Fas (CD95), but not perforin/granzymemediated cytotoxicity. There was no correlation between these divergences and the avidity o
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cd8 cytotoxic t lymphocyte activation by soluble major histocompatibility complex peptide dimers
Journal of Biological Chemistry, 2005Co-Authors: Marek Cebecauer, Philippe Guillaume, Silke Mark, Olivier Michielin, Nicole Boucheron, Michael Bezard, Bruno H Meyer, Jeanmanuel Segura, Horst Vogel, Immanuel F LuescherAbstract:CD8+ cytotoxic T lymphocyte (CTL) can recognize and kill target cells that express only a few cognate major histocompatibility complex class I-peptide (pMHC) complexes. To better understand the molecular basis of this sensitive Recognition process, we studied dimeric pMHC complexes containing linkers of different lengths. Although dimers containing short (10–30-A) linkers efficiently bound to and triggered intracellular calcium mobilization and phosphorylation in cloned CTL, dimers containing long linkers (≥80 A) did not. Based on this and on fluorescence resonance energy transfer experiments, we describe a dimeric binding mode in which two T cell receptors engage in an anti-parallel fashion two pMHC complexes facing each other with their constant domains. This binding mode allows integration of diverse low affinity interactions, which increases the overall binding and, hence, the sensitivity of Antigen Recognition. In proof of this, we demonstrated that pMHC dimers containing one agonist and one null ligand efficiently activate CTL, corroborating the importance of endogenous pMHC complexes in Antigen Recognition.
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effects of epitope modification on t cell receptor ligand binding and Antigen Recognition by seven h 2kd restricted cytotoxic t lymphocyte clones specific for a photoreactive peptide derivative
Journal of Experimental Medicine, 1997Co-Authors: Benedikt M Kessler, Jean-charles Cerottini, Paolo Bassanini, Immanuel F LuescherAbstract:We tested for Antigen Recognition and T cell receptor (TCR)–ligand binding 12 peptide derivative variants on seven H-2Kd–restricted cytotoxic T lymphocytes (CTL) clones specific for a bifunctional photoreactive derivative of the Plasmodium berghei circumsporozoite peptide 252– 260 (SYIPSAEKI). The derivative contained iodo-4-azidosalicylic acid in place of PbCS S-252 and 4-azidobenzoic acid on PbCS K-259. Selective photoactivation of the N-terminal photoreactive group allowed crosslinking to Kd molecules and photoactivation of the orthogonal group to TCR. TCR photoaffinity labeling with covalent Kd–peptide derivative complexes allowed direct assessment of TCR–ligand binding on living CTL. In most cases (over 80%) cytotoxicity (chromium release) and TCR–ligand binding differed by less than fivefold. The exceptions included ( a ) partial TCR agonists (8 cases), for which Antigen Recognition was fivetenfold less efficient than TCR–ligand binding, ( b ) TCR antagonists (2 cases), which were not recognized and capable of inhibiting Recognition of the wild-type conjugate, ( c ) heteroclitic agonists (2 cases), for which Antigen Recognition was more efficient than TCR–ligand binding, and ( d ) one partial TCR agonist, which activated only Fas (CD95), but not perforin/granzymemediated cytotoxicity. There was no correlation between these divergences and the avidity of TCR–ligand binding, indicating that other factors than binding avidity determine the nature of the CTL response. An unexpected and novel finding was that CD8-dependent clones clearly incline more to TCR antagonism than CD8-independent ones. As there was no correlation between CD8 dependence and the avidity of TCR–ligand binding, the possibility is suggested that CD8 plays a critical role in aberrant CTL function.
Esteban Celis - One of the best experts on this subject based on the ideXlab platform.
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fine restriction analysis and inhibition of Antigen Recognition in hla dq restricted t cells by major histocompatibility complex blockers and t cell receptor antagonists
European Journal of Immunology, 1993Co-Authors: Horacio M Serra, Esteban Celis, Claire CrimiAbstract:: The role of polymorphic residues of the beta chain of human histocompatibility leukocyte Antigen-DQw5/w6 in Antigen presentation to a hepatitis B surface Antigen-specific T cell clone was studied. The results obtained demonstrate that the residue situated at position 57 of the beta chain (a valine) is critical for presentation of Antigen by Antigen-presenting cells to the DQ-restricted T cell clone. Experiments were also done to study the feasibility of peptide blocking of Antigen Recognition by DQ-restricted T cells. The results indicate that peptides known to associate with DQ molecules are capable of blocking the presentation of Antigen to the DQ-restricted T cell clone, presumably by competing with Antigen for binding to major histocompatibility complex (MHC) molecules. Moreover, truncations of the stimulatory Antigenic peptide resulted in the production of T cell receptor antagonists, which inhibited the response of the T cells to Antigen at 10-100-fold lower concentrations than conventional MHC blockers. The role of DQ-restricted T cell responses and peptide blocking approaches in autoimmunity are discussed.
C K Hurley - One of the best experts on this subject based on the ideXlab platform.
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limited hla sequence variation outside of Antigen Recognition domain exons of 360 10 of 10 matched unrelated hematopoietic stem cell transplant donor recipient pairs
HLA, 2017Co-Authors: Lihua Hou, Cynthia Vierragreen, A Lazaro, Colleen Brady, M Haagenson, Stephen R Spellman, C K HurleyAbstract:Traditional DNA-based typing focuses primarily on interrogating the exons of human leukocyte Antigen (HLA) genes that form the Antigen Recognition domain (ARD). The relevance of mismatching donor and recipient for HLA variation outside the ARD on hematopoietic stem cell transplantation (HSCT) outcomes is unknown. This study was designed to evaluate the frequency of variation outside the ARD in 10 of 10 (HLA-A, -B, -C, -DRB1, -DQB1) matched unrelated donor transplant pairs (n = 360). Next-generation DNA sequencing was used to characterize both HLA exons and introns for HLA-A, -B, -C alleles; exons 2, 3 and the intervening intron for HLA-DRB1 and exons only for HLA-DQA1 and -DQB1. Over 97% of alleles at each locus were matched for their nucleotide sequence outside of the ARD exons. Of the 4320 allele comparisons overall, only 17 allele pairs were mismatched for non-ARD exons, 41 for noncoding regions and 9 for ARD exons. The observed variation between donor and recipient usually involved a single nucleotide difference (88% of mismatches); 88% of the non-ARD exon variants impacted the amino acid sequence. The impact of amino acid sequence variation caused by substitutions in exons outside ARD regions in D-R pairs will be difficult to assess in HSCT outcome studies because these mismatches do not occur very frequently.
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evaluating the potential impact of mismatches outside the Antigen Recognition site in unrelated hematopoietic stem cell transplantation hla drb1 1454 and drb1 140101
Tissue Antigens, 2009Co-Authors: Y Xiao, Cynthia Vierragreen, M Haagenson, Stephen R Spellman, A M Lazaro, C Masaberg, Sivanesan Dakshanamurthy, C K HurleyAbstract:DNA sequencing of 268 individuals drawn from four US populations carrying two unresolved DRB1*14 alleles differing only outside the Antigen Recognition site identified DRB1*1454 in the majority. A database of 4222 human leukocyte Antigen (HLA)-matched hematopoietic stem cell transplantation donor–recipient pairs was queried to determine the number likely mismatched for DRB1*140101/DRB1*1454 but matched for class I loci. A power calculation suggests that more than 88,000 transplants among European Americans will be needed to identify sufficient 7/8 allele-matched pairs to evaluate the impact of the DRB1*140101/DRB1*1454 mismatch on transplant outcome. Molecular modeling of the HLA-DR interaction with the T-cell receptor and with CD4 suggests that the amino acid substitution distinguishing the two alleles will have minimal impact on alloRecognition.
Deborah Hatherley - One of the best experts on this subject based on the ideXlab platform.
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structure of signal regulatory protein alpha a link to Antigen receptor evolution
Journal of Biological Chemistry, 2009Co-Authors: Deborah Hatherley, Stephen C Graham, Karl Harlos, D I Stuart, A N BarclayAbstract:Abstract Signal-regulatory protein α (SIRPα) is a myeloid membrane receptor that interacts with the membrane protein CD47, a marker of self. We have solved the structure of the complete extracellular portion of SIRPα, comprising three immunoglobulin superfamily domains, by x-ray crystallography to 2.5 A resolution. These data, together with previous data on the N-terminal domain and its ligand CD47 (possessing a single immunoglobulin superfamily domain), show that the CD47-SIRPα interaction will span a distance of around 14 nm between interacting cells, comparable with that of an immunological synapse. The N-terminal (V-set) domain mediates binding to CD47, and the two others are found to be constant (C1-set) domains. C1-set domains are restricted to proteins involved in vertebrate Antigen Recognition: T cell Antigen receptors, immunoglobulins, major histocompatibility complex Antigens, tapasin, and β2-microglobulin. The domains of SIRPα (domains 2 and 3) are structurally more similar to C1-set domains than any cell surface protein not involved in Antigen Recognition. This strengthens the suggestion from sequence analysis that SIRP is evolutionarily closely related to Antigen Recognition proteins.
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structure of signal regulatory protein alpha a link to Antigen receptor evolution
Journal of Biological Chemistry, 2009Co-Authors: Deborah Hatherley, Stephen C Graham, Karl Harlos, D I Stuart, Neil A BarclayAbstract:Signal-regulatory protein alpha (SIRPalpha) is a myeloid membrane receptor that interacts with the membrane protein CD47, a marker of self. We have solved the structure of the complete extracellular portion of SIRPalpha, comprising three immunoglobulin superfamily domains, by x-ray crystallography to 2.5 A resolution. These data, together with previous data on the N-terminal domain and its ligand CD47 (possessing a single immunoglobulin superfamily domain), show that the CD47-SIRPalpha interaction will span a distance of around 14 nm between interacting cells, comparable with that of an immunological synapse. The N-terminal (V-set) domain mediates binding to CD47, and the two others are found to be constant (C1-set) domains. C1-set domains are restricted to proteins involved in vertebrate Antigen Recognition: T cell Antigen receptors, immunoglobulins, major histocompatibility complex Antigens, tapasin, and beta2-microglobulin. The domains of SIRPalpha (domains 2 and 3) are structurally more similar to C1-set domains than any cell surface protein not involved in Antigen Recognition. This strengthens the suggestion from sequence analysis that SIRP is evolutionarily closely related to Antigen Recognition proteins.
Jeanmanuel Segura - One of the best experts on this subject based on the ideXlab platform.
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increased mobility of major histocompatibility complex i peptide complexes decreases the sensitivity of Antigen Recognition
Journal of Biological Chemistry, 2008Co-Authors: Philippe Guillaume, Silke Mark, Jeanmanuel Segura, Danijel Dojcinovic, Alexandre Johannsen, Giovanna Bosshard, Georgi S Angelov, Daniel F Legler, Horst VogelAbstract:CD8+ cytotoxic T lymphocytes (CTL) can recognize and kill target cells expressing only a few cognate major histocompatibility complex (MHC) I-peptide complexes. This high sensitivity requires efficient scanning of a vast number of highly diverse MHC I-peptide complexes by the T cell receptor in the contact site of transient conjugates formed mainly by nonspecific interactions of ICAM-1 and LFA-1. Tracking of single H-2Kd molecules loaded with fluorescent peptides on target cells and nascent conjugates with CTL showed dynamic transitions between states of free diffusion and immobility. The immobilizations were explained by association of MHC I-peptide complexes with ICAM-1 and strongly increased their local concentration in cell adhesion sites and hence their scanning by T cell receptor. In nascent immunological synapses cognate complexes became immobile, whereas noncognate ones diffused out again. Interfering with this mobility modulation-based concentration and sorting of MHC I-peptide complexes strongly impaired the sensitivity of Antigen Recognition by CTL, demonstrating that it constitutes a new basic aspect of Antigen presentation by MHC I molecules.
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cd8 cytotoxic t lymphocyte activation by soluble major histocompatibility complex peptide dimers
Journal of Biological Chemistry, 2005Co-Authors: Marek Cebecauer, Philippe Guillaume, Silke Mark, Olivier Michielin, Nicole Boucheron, Michael Bezard, Bruno H Meyer, Jeanmanuel Segura, Horst Vogel, Immanuel F LuescherAbstract:CD8+ cytotoxic T lymphocyte (CTL) can recognize and kill target cells that express only a few cognate major histocompatibility complex class I-peptide (pMHC) complexes. To better understand the molecular basis of this sensitive Recognition process, we studied dimeric pMHC complexes containing linkers of different lengths. Although dimers containing short (10–30-A) linkers efficiently bound to and triggered intracellular calcium mobilization and phosphorylation in cloned CTL, dimers containing long linkers (≥80 A) did not. Based on this and on fluorescence resonance energy transfer experiments, we describe a dimeric binding mode in which two T cell receptors engage in an anti-parallel fashion two pMHC complexes facing each other with their constant domains. This binding mode allows integration of diverse low affinity interactions, which increases the overall binding and, hence, the sensitivity of Antigen Recognition. In proof of this, we demonstrated that pMHC dimers containing one agonist and one null ligand efficiently activate CTL, corroborating the importance of endogenous pMHC complexes in Antigen Recognition.