Alloreactivity, Antigen Recognition and T‐Cell Selection: Three Diverse T‐Cell Recognition Problems with a Common Solution

Joyce, Sebastian; Nathenson, Stanley G.

doi:10.1111/j.1600-065x.1996.tb00930.x

Cited by 24 publications

(16 citation statements)

References 252 publications

(213 reference statements)

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“…The binding specificities of individual phage clones and soluble Fab were determined by ELISA using biotinylated scMHC/peptide complexes as described previously [24]. The HLA-A2-restricted peptides used for specificity studies of the Fab phage clones or purified Fab Ab:EBV (280-288), gp100 (280-288), hTERT (540-548), gp100 (209-217), hTERT (865-873), Gag (77-85), Pol (476-484), MART (26)(27)(28)(29)(30)(31)(32)(33)(34)(35), XAGE, TARP, TAX (11)(12)(13)(14)(15)(16)(17)(18)(19). Fluorescently labeled tetrameric Fab Ab were generated by site-specific biotinylation at the C terminus of the Fab as previously described [24].…”

Section: Methodsmentioning

confidence: 99%

“…Peptide binding stabilizes class I MHC molecules and permits their movement out of the ER, through the Golgi, to the cell surface. This pathway ensures that any cell synthesizing viral proteins can be marked for recognition and killing by CD8 1 CTL [11,12]. Among all the pp65 peptides, CMV-specific CTL activity in HLA-A2-positive individuals was found to be mainly directed to the peptide pp65 495-503 NLVPMVATV [13].…”

Section: Introductionmentioning

confidence: 99%

“…be marked for recognition and killing by CD8 1 CTL [11,12]. Among all the pp65 peptides, CMV-specific CTL activity in HLA-A2-positive individuals was found to be mainly directed to the peptide pp65 495-503 NLVPMVATV [13].…”

mentioning

confidence: 99%

“…No staining was observed, confirming the H9 specificity (data not shown). (11)(12)(13)(14)(15)(16)(17)(18)(19). (C) Binding of H9 to peptide-pulsed APC.…”

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confidence: 99%

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Direct visualization of the dynamics of antigen presentation in human cells infected with cytomegalovirus revealed by antibodies mimicking TCR specificity

et al. 2010

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There are no direct means to study class I MHC presentation in human normal or diseased cells. Using CMV-infected human cells and applying novel mAb that mimic T-cell receptor specificity directed toward the immunogenic epitope of the viral pp65 protein presented on HLA-A2 molecules, we directly imaged the dynamics of Ag presentation in infected cells. We demonstrate that following infection large intracellular pools of HLA-A2/pp65 complexes are localized to the Golgi. These HLA-A2/pp65 pools account for the majority of total HLA-A2 molecules in infected cells. Interestingly, these large pools are sequestered inside infected cells and only a small portion of them are exported to the cell surface. Virus-induced class I MHC down-regulation did not affect the intracellular pool of HLA-A2/ pp65 complexes. Our data also suggest that proteasome function influences the release of class I complexes to the membrane. We present herein a new and direct molecular tool to study the dynamics of viral Ag presentation that may further elucidate the balance between immune response versus viral escape.Key words: Ab . Ag presentation/processing . MHC . Virology Supporting Information available online IntroductionImmunity to CMV is complex and involves humoral and cellmediated responses [1][2][3][4][5]. Studies showed that both NK cells and CTL are of primary importance in the prevention of recurrence [6][7][8]. Many gene products participate in generating the CTL response, but the high frequencies of the viral protein pp65 found in subsequent studies showed that this protein is the chief target of the CTL-mediated immune response [9,10]. Cytosolic proteins, usually synthesized in the cells, such as these viral proteins, enter the class I MHC pathway of Ag presentation. The proteasome is a cytoplasmic multiprotein complex that proteolytically degrades ubiquitinated cytoplasmic proteins and probably generates a large portion of the peptides destined for display by class I MHC molecules. Peptides are delivered from the cytoplasm to the ER by the TAP molecules. Newly formed class I MHC dimmers in the ER associate with and bind peptides delivered by the TAP. Peptide binding stabilizes class I MHC molecules and permits their movement out of the ER, through the Golgi, to the cell surface. This pathway ensures that any cell synthesizing viral proteins can 1552be marked for recognition and killing by CD8 1 CTL [11,12]. Among all the pp65 peptides, CMV-specific CTL activity in HLA-A2-positive individuals was found to be mainly directed to the peptide pp65 495-503 NLVPMVATV [13].Characterization of class I MHC/peptide presentation is essential for studying the relationships between immunity and viral escape. However, there are no direct means available to study class I MHC/peptide presentation; for example, study of viralderived peptide/MHC complexes on the surface and inside cells during the course of infection. mAb with peptide-specific, MHCrestricted recognition patterns, termed TCR-like Ab, are currently the only tool for such studies. ...

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

“…No staining was observed, confirming the H9 specificity (data not shown). (11)(12)(13)(14)(15)(16)(17)(18)(19). (C) Binding of H9 to peptide-pulsed APC.…”

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confidence: 99%

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Direct visualization of the dynamics of antigen presentation in human cells infected with cytomegalovirus revealed by antibodies mimicking TCR specificity

et al. 2010

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“…T he ␣␤ TCR recognizes Ags as short peptides bound to MHC molecules present on the surface of APCs (1,2). The interaction between the TCR and MHC/peptide complex usually leads to the activation of the T cell, which involves its proliferation and cytokine release.…”

mentioning

confidence: 99%

Altered Peptide Ligand-Mediated TCR Antagonism Can Be Modulated by a Change in a Single Amino Acid Residue Within the CDR3β of an MHC Class I-Restricted TCR

Kalergis

Nathenson

2000

The Journal of Immunology

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The Ag receptor of cytotoxic CD8+ T lymphocytes recognizes peptides of 8–10 aa bound to MHC class I molecules. This Ag recognition event leads to the activation of the CD8+ lymphocyte and subsequent lysis of the target cell. Altered peptide ligands are analogues derived from the original antigenic peptide that commonly carry amino acid substitutions at TCR contact residues. TCR engagement by these altered peptide ligands usually impairs normal T cell function. Some of these altered peptide ligands (antagonists) are able to specifically antagonize and inhibit T cell activation induced by the wild-type antigenic peptide. Despite significant advances made in understanding TCR antagonism, the molecular interactions between the TCR and the MHC/peptide complex responsible for the inhibitory activity of antagonist peptides remain elusive. To approach this question, we have identified altered peptide ligands derived from the vesicular stomatitis virus peptide (RGYVYQGL) that specifically antagonize an H-2Kb/vesicular stomatitis virus-specific TCR. Furthermore, by site-directed mutagenesis, we altered single amino acid residues of the complementarity-determining region 3 of the β-chain of this TCR and tested the effect of these point mutations on Ag recognition and TCR antagonism. Here we show that a single amino acid change on the TCR CDR3β loop can modulate the TCR-antagonistic properties of an altered peptide ligand. Our results highlight the role of the TCR complementarity-determining region 3 loops for controlling the nature of the T cell response to TCR/altered peptide ligand interactions, including those leading to TCR antagonism.

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Identification of endogenous peptides recognized byin vivo orin vitro generated alloreactive cytotoxic T lymphocytes: distinct characteristics correlated with CD8 dependence

et al. 2001

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Alloreactivity, Antigen Recognition and T‐Cell Selection: Three Diverse T‐Cell Recognition Problems with a Common Solution

Cited by 24 publications

References 252 publications

Direct visualization of the dynamics of antigen presentation in human cells infected with cytomegalovirus revealed by antibodies mimicking TCR specificity

Direct visualization of the dynamics of antigen presentation in human cells infected with cytomegalovirus revealed by antibodies mimicking TCR specificity

Altered Peptide Ligand-Mediated TCR Antagonism Can Be Modulated by a Change in a Single Amino Acid Residue Within the CDR3β of an MHC Class I-Restricted TCR

Identification of endogenous peptides recognized byin vivo orin vitro generated alloreactive cytotoxic T lymphocytes: distinct characteristics correlated with CD8 dependence

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