Competitive Inhibition In Vivo and Skewing of the T Cell Repertoire of Antigen-Specific CTL Priming by an Anti-Peptide-MHC Monoclonal Antibody

Chung, Doo Hyun; Belyakov, Igor M.; Derby, Michael A.; Wang, Jian; Boyd, Lisa F.; Berzofsky, Jay A.; Margulies, David H.

doi:10.4049/jimmunol.167.2.699

Cited by 8 publications

(7 citation statements)

References 62 publications

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“…Still, these tools can also prove useful in understanding the mechanisms that regulate tumor Ag processing and presentation through their ability to detect and quantify the number of specific complexes. Several other groups have reported on Abs with similar specificity for peptide-MHC targets (9,11,42,43). Recently, the groups of Hoogenboom and Reiter (13, 14, 44 -46) have created Ab libraries using phage display to isolate singlechain variable fragments that specifically recognize HLA class I molecules presenting peptide fragments from several TAAs, including telomerase, gp100, and MAGE-1.…”

Section: Discussionmentioning

confidence: 99%

“…Characterization of 1B8 TCRm binding specificity. HLA-A2 tetramer complexes were loaded with 0.1 g of each of the following peptides: Her2 (369) (369 -377 KIFGSLAFL), VLQ (44) (44)(45)(46)(47)(48)(49)(50)(51)(52), eIF4G (720) (720 -748 VLMTEDIKL), and TMT (40) (40)(41)(42)(43)(44)(45)(46)(47)(48). Recombinant proteins were detected by staining with a 1B8 TCR mAb specific for the Her-2 (369) -A2 complex (A), a 3F9 TCRm mAb specific for the TMT (40) -A2 complex (B), and a BB7.2 mAb specific for HLA-A2.1 (C) followed by ELISA as described in Material and Methods.…”

Section: Generation and Reactivity Of 1b8 Tcr Mimic Mabmentioning

confidence: 99%

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Levels of Specific Peptide-HLA Class I Complex Predicts Tumor Cell Susceptibility to CTL Killing

Weidanz

Nguyen²,

Woodburn³

et al. 2006

The Journal of Immunology

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Recognition of tumor-associated Ags (TAAs) on tumor cells by CTLs and the subsequent tumor cell death are assumed to be dependent on TAA protein expression and to correlate directly with the level of peptide displayed in the binding site of the HLA class I molecule. In this study we evaluated whether the levels of Her-2/neu protein expression on human tumor cell lines directly correlate with HLA-A*0201/Her2/neu peptide presentation and CTL recognition. We developed a TCR mimic (TCRm) mAb designated 1B8 that specifically recognizes the HLA-A2.1/Her2/neu peptide (369–377) (Her2(369)-A2) complex. TCRm mAb staining intensity varied for the five human tumor cell lines analyzed, suggesting quantitative differences in levels of the Her2(369)-A2 complex on these cells. Analysis of tumor cell lines pretreated with IFN-γ and TNF-α for Her2/neu protein and HLA-A2 molecule expression did not reveal a direct correlation between the levels of Her2/neu Ag, HLA-A2 molecule, and Her2(369)-A2 complex expression. However, compared with untreated cells, cytokine-treated cell lines showed an increase in Her2(369)-A2 epitope density that directly correlated with enhanced tumor cell death (p = 0.05). Although a trend was observed between tumor cell lysis and the level of the Her2(369)-A2 complex for untreated cells, the association was not significant. These findings suggest that tumor cell susceptibility to CTL-mediated lysis may be predicted based on the level of specific peptide-MHC class I expression rather than on the total level of TAA expression. Further, these studies demonstrate the potential of the TCRm mAb for validation of endogenous HLA-peptide epitopes on tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Generation and Reactivity Of 1b8 Tcr Mimic Mabmentioning

confidence: 99%

Levels of Specific Peptide-HLA Class I Complex Predicts Tumor Cell Susceptibility to CTL Killing

Weidanz

Nguyen²,

Woodburn³

et al. 2006

The Journal of Immunology

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“…For this reason, we believe that rVSVs, particularly VSV-Env, may have practical application in basic immunological studies of foreign proteins. For example, the antibody KP15 binds the D d MHC-p18-I10 complex and blocks induction of CTL recognizing this complex (9). VSVEnv might be useful in testing the effects of KP15 without the need for in vitro restimulation.…”

Section: Discussionmentioning

confidence: 99%

High-Level Primary CD8⁺T-Cell Response to Human Immunodeficiency Virus Type 1 Gag and Env Generated by Vaccination with Recombinant Vesicular Stomatitis Viruses

Haglund

Leiner

Kerksiek

et al. 2002

J Virol

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We investigated the primary cellular immune responses to human immunodeficiency virus type 1 (HIV-1) Env and Gag proteins elicited by recombinant vesicular stomatitis viruses (rVSVs). The primary response to Env peaked 5 to 7 days after intraperitoneal vaccination, at which time 40% of CD8 ؉ cells were Env tetramer positive and activated (CD62L Lo ). These freshly isolated cells actively lysed target cells pulsed with the p18-I10 peptide and secreted gamma interferon and tumor necrosis factor alpha after stimulation with the Env p18-I10 peptide. The primary response to Env elicited by rVSVs was sixfold higher than that elicited by recombinant vaccinia viruses (rVVs) at 5 days postvaccination. An intranasal route of vaccination with VSV-Env also elicited a strong primary response to Env. The primary immune response to Gag elicited by rVSV peaked 7 days after vaccination, at which time 3% of CD8 ؉ cells were Gag tetramer positive and CD62L Lo and functional by intracellular cytokine staining. This response was eightfold higher than that elicited by rVV expressing Gag. VSV-GagEnv, which expresses both Gag and Env from a single recombinant, also induced strong cytotoxic T-lymphocyte (CTL) responses to both Env and Gag. Our quantitative analyses illustrate the potency of the VSV vector system in CTL induction.

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“…Endogenous Antigen-Monoclonal antibodies have been used previously to examine the presentation of specific pMHC (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Generation of such reagents is laborious and involves extensive screening of monoclonal antibodies, although some recent technical advances may facilitate this process (34,35).…”

Section: Tcr Multimers Can Sense Quantitative Modifications Of Antigementioning

confidence: 99%

Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition

Laugel

Boulter

Lissin³

et al. 2005

Journal of Biological Chemistry

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The use of recombinant T cell receptors (TCRs) to target therapeutic interventions has been hindered by the naturally low affinity of TCR interactions with peptide major histocompatibility complex ligands. Here, we use multimeric forms of soluble heterodimeric ␣␤ TCRs for specific detection of target cells pulsed with cognate peptide, discrimination of quantitative changes in antigen display at the cell surface, identification of virusinfected cells, inhibition of antigen-specific cytotoxic T lymphocyte activation, and identification of cross-reactive peptides. Notably, the A6 TCR specific for the immunodominant HLA A2-restricted human T cell leukemia virus type 1 Tax 11-19 epitope bound to HLA A2-HuD 87-95 (K D 120 M by surface plasmon resonance), an epitope implicated as a causal antigen in the paraneoplastic neurological degenerative disorder anti-Hu syndrome. A mutant A6 TCR that exhibited dramatically increased affinity for cognate antigen (K D 2.5 nM) without enhanced cross-reactivity was generated; this TCR demonstrated potent biological activity even as a monomeric molecule. These data provide insights into TCR repertoire selection and delineate a framework for the selective modification of TCRs in vitro that could enable specific therapeutic intervention in vivo.Peptide major histocompatibility complex (pMHC) 1 antigens displayed on the surface of target cells are recognized by T cells via their specific T cell receptor (TCR) (1). The TCR coreceptors CD8 or CD4 bind to invariant domains of pMHC class I (pMHCI) or pMHC class II (pMHCII) and are known to facilitate the process of antigen recognition by T cells (2). Recent advances have enabled the generation of high quality soluble TCR, pMHCI, pMHCII, CD8, and CD4 proteins; these in turn have allowed the biophysical characterization of the interactions between these molecules. Accordingly, the TCR and CD4/8 co-receptors have been shown to have very low affinities (K D ϳ 10 Ϫ3 -10 Ϫ6 M) for cognate pMHC. Despite these low affinity interactions, however, the process of antigen engagement can initiate T cell recognition of antigen-presenting cells (APCs) bearing fewer than 10 copies of a specific pMHC complex (3, 4). The mechanisms by which these weak recognition events result in such exquisite sensitivity are not fully understood.The production of soluble recombinant ␣␤ T cell receptors has proved challenging. The main technical pitfall is heterodimeric instability in the absence of anchoring transmembrane domains and ␣/␤ pairing through an interchain disulfide bond. One of the commonest protein engineering strategies used in TCR studies to date has been the construction of singlechain TCRs. This technique, which takes advantage of the structural similarities between antibodies and TCRs, is based upon the single-chain Fv technology used to generate antibody fragments (5). In short, for the TCR it involves the cloning and expression of a unique chimerical open reading frame where the variable (V) ␣ and V␤ domains are paired with a protein linker (6, 7). Thes...

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Competitive Inhibition In Vivo and Skewing of the T Cell Repertoire of Antigen-Specific CTL Priming by an Anti-Peptide-MHC Monoclonal Antibody

Cited by 8 publications

References 62 publications

Levels of Specific Peptide-HLA Class I Complex Predicts Tumor Cell Susceptibility to CTL Killing

Levels of Specific Peptide-HLA Class I Complex Predicts Tumor Cell Susceptibility to CTL Killing

High-Level Primary CD8⁺T-Cell Response to Human Immunodeficiency Virus Type 1 Gag and Env Generated by Vaccination with Recombinant Vesicular Stomatitis Viruses

Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition

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Competitive Inhibition In Vivo and Skewing of the T Cell Repertoire of Antigen-Specific CTL Priming by an Anti-Peptide-MHC Monoclonal Antibody

Cited by 8 publications

References 62 publications

Levels of Specific Peptide-HLA Class I Complex Predicts Tumor Cell Susceptibility to CTL Killing

Levels of Specific Peptide-HLA Class I Complex Predicts Tumor Cell Susceptibility to CTL Killing

High-Level Primary CD8+T-Cell Response to Human Immunodeficiency Virus Type 1 Gag and Env Generated by Vaccination with Recombinant Vesicular Stomatitis Viruses

Design of Soluble Recombinant T Cell Receptors for Antigen Targeting and T Cell Inhibition

Contact Info

Product

Resources

About

High-Level Primary CD8⁺T-Cell Response to Human Immunodeficiency Virus Type 1 Gag and Env Generated by Vaccination with Recombinant Vesicular Stomatitis Viruses