Quantitative determination of TCR cross-reactivity using peptide libraries and protein databases

Hiemstra, Hoebert S.; Veelen, Peter A. van; Willemen, Sabine J. M.; Benckhuijsen, Willemien E.; Geluk, Annemieke; Vries, R. R. P. De; Roep, Bart O.; Drijfhout, Jan W.

doi:10.1002/(sici)1521-4141(199908)29:08<2385::aid-immu2385>3.0.co;2-b

Cited by 30 publications

(20 citation statements)

References 16 publications

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“…A T-cell clone was isolated from a prediabetic subject 4 years prior to the clinical manifestation of diabetes [81]. This clone was used to define the antigen recognition pattern by screening a random synthetic peptide library dedicated to bind to the relevant HLA restriction element (HLA-DR3 in this case) [82,83,84]. A peptide of human cytomegalovirus major DNA-binding protein was identified that stimulated the autoreactive T-cell clone.…”

Section: Genetic and Environmental Factors Associated With T-cell Autmentioning

confidence: 99%

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

2003

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Section: Genetic and Environmental Factors Associated With T-cell Autmentioning

confidence: 99%

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

2003

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“…Third, TCR multimers were used to screen for and identify syngeneic cross-reactive pMHCI ligands (Fig. 6); this approach eliminates the effects of adhesion/costimulatory molecular interactions that potentially confound cellular screening assays (47,48) and has recently been validated in class II-restricted systems (49). Surface plasmon resonance studies confirmed binding, with measured affinities for both HLA A2-Tel1p and HLA A2-HuD 87-95 lying at the lower end of the spectrum of previously defined TCR/pMHC interactions (22) (Fig.…”

Section: Functional Optimization Of Soluble Tcrsmentioning

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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“…All other peptides used in this study were synthesized on an automated multiple peptide synthesizer (Syroll, Multisyntech, Germany) and isolated as previously described (22). The purity of the peptides was determined by analytical reverse phase HPLC as previously described (22) and proved to be at least 70% (UV, 214 nm). The integrity of the peptides was determined by mass spectroscopy as previously described (22).…”

Section: Peptides and Mabsmentioning

confidence: 99%

“…The purity of the peptides was determined by analytical reverse phase HPLC as previously described (22) and proved to be at least 70% (UV, 214 nm). The integrity of the peptides was determined by mass spectroscopy as previously described (22). mAbs B8.11.2 specific for HLA-DR (23) and SPVL3 specific for HLA-DQ (24) were provided by Arend Mulder (Leiden University Medical Center, Leiden, The Netherlands).…”

Section: Peptides and Mabsmentioning

confidence: 99%

An HLA-DRB1-Derived Peptide Associated with Protection Against Rheumatoid Arthritis Is Naturally Processed by Human APCs

Snijders

Elferink

Geluk

et al. 2001

The Journal of Immunology

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Predisposition to rheumatoid arthritis (RA) is thought to be associated with HLA-DR1, -DR4, and -DR10. However, many epidemiological observations are better explained by a model in which the DQ alleles that are linked to these DR alleles, i.e., DQ5, DQ7, and DQ8, predispose to RA, while certain DR alleles have a dominant protective effect. All protective DRB1 alleles, e.g., *0402, *1301, and *1302, encode a unique motif, 70DERAA74. The protection may be explained by the presentation of DRB1-derived peptides by DQ to immunoregulatory T cells, because it was demonstrated in various autoimmune disease models that T cell responses to certain self-Ags can be involved in disease suppression. The aim of this study was to analyze whether peptides carrying the DERAA motif are naturally processed by human APC and presented in the context of the RA-predisposing DQ. Using a synthetic peptide carrying the DRB1*0402-derived sequence 65KDILEDERAAVDTYC79, we generated DERAA peptide-specific DQ-restricted T cell clones (TCC) from a DQ8 homozygous individual carrying DERAA-negative DR4 alleles. By analyzing the proliferation of these TCC, we demonstrated natural processing and presentation of the DERAA sequence by the APC of all the individuals (n = 12) carrying a DERAA-positive DRB1 allele and either DQ8 or the DQ8-related DQ7. Using a panel of truncated synthetic peptides, we identified the sequence 67(I)LEDERAAVD(TY)78 as the minimal determinant for binding to DQ8 and for recognition by the TCC. These findings support a model in which self-MHC-derived peptide can modulate predisposition to autoimmune disease in humans.

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Quantitative determination of TCR cross-reactivity using peptide libraries and protein databases

Cited by 30 publications

References 16 publications

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

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

An HLA-DRB1-Derived Peptide Associated with Protection Against Rheumatoid Arthritis Is Naturally Processed by Human APCs

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