Amino acid residues that flank core peptide epitopes and the extracellular domains of CD4 modulate differential signaling through the T cell receptor

1994 ◽  
Vol 10 (8) ◽  
pp. 264 ◽  
Author(s):  
D.A.A. Vignali ◽  
J.L. Strominger
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Amino Acid Residues ◽  
Peptide Epitopes ◽  
Extracellular Domains ◽  
Differential Signaling ◽  
Core Peptide

scholarly journals Amino acid residues that flank core peptide epitopes and the extracellular domains of CD4 modulate differential signaling through the T cell receptor.

1994 ◽  
Vol 179 (6) ◽  
pp. 1945-1956 ◽  
Author(s):  
D A Vignali ◽  
J L Strominger
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Class Ii ◽  
Peptide Epitopes ◽  
Differential Signaling ◽  
Effective Signal

Hen egg lysozyme 52-61-specific CD4+ T cells responded by interleukin 2 (IL-2) secretion to any peptide containing this epitope regardless of length of NH2- and COOH-terminal composition. However, CD4- variants could only respond to peptides containing the two COOH-terminal tryptophans at positions 62 and 63. Substitutions at these positions defined patterns of reactivity that were specific for individual T cells inferring a T cell receptor (TCR)-based phenomenon. Thus, the fine specificity of major histocompatibility complex (MHC)-peptide recognition by the TCR was dramatically affected by CD4 and the COOH-terminal peptide composition. Peptides that failed to induce IL-2 secretion in the CD4- variants nevertheless induced strong tyrosine phosphorylation of CD3 zeta. Thus, whereas the TCR still recognized and bound to the MHC class II-peptide complex resulting in protein phosphorylation, this interaction failed to induce effective signal transduction manifested by IL-2 secretion. This provides a clear example of differential signaling mediated by peptides known to be naturally processed. In addition, the external domains of CD4, rather than its cytoplasmic tail, were critical in aiding TCR recognition of all peptides derived from a single epitope. These data suggest that the nested flanking residues, which are present on MHC class II but not class I bound peptides, are functionally relevant.

scholarly journals Functional Recognition by CD8+ T Cells of Epitopes with Amino Acid Variations Outside Known MHC Anchor or T Cell Receptor Recognition Residues

2020 ◽  
Vol 21 (13) ◽  
pp. 4700
Author(s):  
Kirsty L. Wilson ◽  
Sue D. Xiang ◽  
Magdalena Plebanski
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cross Reactivity ◽  
Altered Peptide Ligand ◽  
Peptide Epitope ◽  
Peptide Epitopes ◽  
Contact Residues

Peptide-based vaccines can be safer and more cost effective than whole organism vaccines. Previous studies have shown that inorganic polystyrene nanoparticles (PSNPs) covalently conjugated to the minimal immunodominant peptide epitope from murine liver stage malaria (SYIPSAEKI) induced potent CD8+ T cell responses. Many pathogens, including malaria, have polymorphic T cell epitope regions. Amino acid changes in positions that are contact residues for the T cell receptor (TCR) often alter the specific cross-reactivity induced by the peptide antigen, and it is largely assumed that changes outside of these residues have little impact. Herein, each amino acid residue (except major histocompatibility complex (MHC) anchors) was systematically changed to an alanine. Peptide epitopes with altered amino acids outside T cell contact residues were still recognized by T cells induced by PSNPs-SYIPSAEKI (KI) vaccines, albeit at lower levels, except for the variant SYIPSAAKI (A7). PSNPs-SYIPSAAKI vaccines further elicited high responses to the index KI peptide. None of the epitopes displayed altered peptide ligand (APL) antagonism in vitro, and re-stimulating SYIPSAEKI and SYIPSAAKI together synergistically enhanced IFN-γ production by the T cells. These results show epitope variation in non-TCR recognition residues can have effects on T cell reactivity, suggesting that such natural variation may also be driven by immune pressure. Additionally, when re-modelling peptides to enhance the cross-reactivity of vaccines, both TCR recognition and non-recognition residues should be considered.

P134 Amino acid sequences of T cell receptor reacting against multiple myeloma

Blood Reviews ◽  
2007 ◽  
Vol 21 ◽  
pp. S129
Author(s):  
S. Dudova ◽  
L. Kovarova ◽  
R. Horvath ◽  
M. Penka ◽  
R. Hajek ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Amino Acid Sequences

Developing and validating an approach for diagnosing and prognosticating cancer from biochemical motifs in T-cell receptors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15260-e15260
Author(s):  
Jared L Ostmeyer ◽  
Lindsay G Cowell ◽  
Scott Christley
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Receptors ◽  
Ovarian Tissue ◽  
Cell Receptor ◽  
Healthy Tissue ◽  
Cervical Lesions ◽  
Cell Receptors ◽  
Biochemical Features

e15260 Background: Immune repertoire deep sequencing allows profiling T-cell populations and enables novel approaches to diagnose and prognosticate cancer by identifying T-cell receptor sequence patterns associated with clinical phenotypes and outcomes. Methods: Our goal is to develop a method to diagnose and prognosticate cancer using sequenced T-cell receptors. To determine how to profile the specificity of a T-cell receptor, we analyze 3D X-ray crystallographic structures of T-cell receptors bound to antigen. We observe a contiguous strip typically 4 amino acid residues in length from the complimentary determining region 3 (CDR3) lying in direct contact with the antigen. Based on this observation, we extract 4 residue long snippets from every receptor’s CDR3 and represent each snippet using biochemical features encoded by its amino acid sequence. The biochemical features are combined with information about the abundance of the snippet or the receptor and scored using a machine learning based approach. Each predictive model is fitted and validated under the requirement that at least one positively labelled snippet appears per tumor and no positively labelled snippets appear in healthy tissue. Results: Using a patient-holdout cross-validation, we fit predictive models to distinguish: 1. colorectal tumors from healthy tissue matched controls with 93% accuracy, 2. breast tumors from healthy tissue matched controls with 94% accuracy, 3. ovarian tumors from non-cancer patient ovarian tissue with 95% accuracy (80% accuracy on a blinded follow-up cohort) 4. and regression of preneoplastic cervical lesions over 1 year in advance with 96% accuracy. Conclusions: Immune repertoires can be used to diagnose and prognosticate cancer.

scholarly journals Influence of the NH2-terminal Amino Acid of the T Cell Receptor α Chain on Major Histocompatibility Complex (MHC) Class II + Peptide Recognition

1997 ◽  
Vol 185 (11) ◽  
pp. 1919-1927 ◽  
Author(s):  
Jeffrey L. Seibel ◽  
Nancy Wilson ◽  
Haruo Kozono ◽  
Philippa Marrack ◽  
John W. Kappler
Keyword(s):  
Major Histocompatibility Complex ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Wild Type ◽  
Terminal Amino Acid ◽  
Histocompatibility Complex ◽  
Terminal Amino ◽  
Α Chain

The α/β T cell receptor (TCR) recognizes peptide fragments bound in the groove of major histocompatibility complex (MHC) molecules. We modified the TCR α chain from a mouse T cell hybridoma and tested its ability to reconstitute TCR expression and function in an α chain–deficient variant of the hybridoma. The modified α chain differed from wild type only in its leader peptide and mature NH2-terminal amino acid. Reconstituted cell surface TCR complexes reacted normally with anti-TCR and anti-CD3 antibodies. Although cross-linking of this TCR with an antibody to the TCR idiotype elicited vigorous T cell hybridoma activation, stimulation with its natural MHC + peptide ligand did not. We demonstrated that this phenotype could be reproduced simply by substituting the glutamic acid (E) at the mature NH2 terminus of the wild type TCR α chain with aspartic acid (D). The substitution also dramatically reduced the affinity of soluble α/β-TCR heterodimers for soluble MHC + peptide molecules in a cell-free system, suggesting that it did not exert its effect simply by disrupting TCR interactions with accessory molecules on the hybridoma. These results demonstrate for the first time that amino acids which are not in the canonical TCR complementarity determining regions can be critical in determining how the TCR engages MHC + peptide.

scholarly journals T Cell Receptor Beta-Chain Profiling of Tumor Tissue, Peripheral Blood and Regional Lymph Nodes From Patients With Papillary Thyroid Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Yizeng Wang ◽  
Yuanchao Liu ◽  
Li Chen ◽  
Zuoyu Chen ◽  
Xiaoning Wang ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Acid Level ◽  
Amino Acid Level ◽  
Cell Receptor ◽  
Papillary Thyroid

Objective: To study the characteristics of the T cell receptor (TCR) repertoire in cancer tissue, peripheral blood and regional lymph nodes (LNs) from patients with papillary thyroid carcinoma (PTC).Methods: PTC tissue, peripheral blood mononuclear cells (PBMCs) and regional LNs of six patients with papillary thyroid carcinoma were harvested. T cell receptor beta-chain (TCRβ) profiling was performed though high-throughput sequencing (HTS), and IMonitor, MiXCR and VDJtools were used to analyze the characteristics of the TCR repertoire.Results: The results of IMonitor and those of MiXCR and VDJtools were very similar. The unique CDR3 of TCRβ from LNs was higher than that of PBMCs, and the CDR3 of TCRβ from LNs was higher than that of PTC tissue. Shannon's diversity index, D50, inverse Simpson index_mean and normalized Shannon's diversity index_mean of CDR3 from LNs were higher than those of PTCs and PBMCs. The HEC (high expansion clones) rate of CDR3 sequences at the amino acid level in PTC tissue was higher than that of PBMCs, which was higher than that of LNs. The V-J HEC rate of CDR3 was highest in PTC tissue, followed by PBMCs and LNs.Conclusion: TCR CDR3 profiling showed differences among and within the PBMCs, PTC tissues and regional LNs of PTC, including unique CDR3, CDR3 HEC at the amino acid level, CDR3 V-J HEC at the amino acid level, Shannon's diversity index and D50. The TCRβ repertoire of PTC tissue, peripheral blood and regional LNs of PTC provide a reference for further study of immunity mechanisms against PTC.

scholarly journals Antigen experience relaxes the organisational structure of the T cell receptor repertoire

2021 ◽  
Author(s):  
Michal Mark ◽  
Shlomit Reich-Zeliger ◽  
Erez Greenstein ◽  
Dan Reshef ◽  
Asaf Madi ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Receptor Repertoire ◽  
Adult Mice ◽  
High Level ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire

The creation and evolution of the T cell receptor repertoire within an individual combines stochastic and deterministic processes. We systematically examine the structure of the repertoire in different T cell subsets in young, adult and LCMV infected mice, from the perspective of variable gene usage, nucleotide sequences and amino acid motifs. Young individuals share a high level of organization, especially in the frequency distribution of variable genes and amino acid motifs. In adult mice, this structure relaxes and is replaced by idiotypic evolution of the effector and regulatory repertoire. The repertoire of CD4+ regulatory T cells was more similar to naïve cells in young mice, but became more similar to effectors with age. Finally, we observed a dramatic restructuring of the repertoire following infection with LCMV. We hypothesize that the stochastic process of recombination and thymic selection initially impose a strong structure to the repertoire, which gradually relaxes following asynchronous responses to different antigens during life.

Alloreactivity as a Source of High Avidity T Cell Clones Specific for Cancer Testis-Antigens Associated with Multiple Myeloma: Prospects for Adoptive Immunotherapy with Primary T Cells Redirected toward Multiple Myeloma by T Cell Receptor Gene Transfer.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3712-3712
Author(s):  
Holger Kronig ◽  
Kathrin Hofer ◽  
Julia Neudorfer ◽  
Christian Peschel ◽  
Helga Bernhard
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
High Avidity ◽  
Peptide Epitopes ◽  
Ct Antigen ◽  
Ct Antigens ◽  
Cancer Testis

Abstract Cancer testis (CT)-antigens belong to a class of tumor antigens that are aberrantly expressed in a variety of hematological malignancies including multiple myeloma. Owing to their restricted gene expression, CT-antigens represent potential target antigens for immunotherapeutical approaches such as vaccination and adoptive T cell transfer. As the CT-antigens are self antigens, the majority of CT-antigen-specific autologous T cells display a low avidity T cell receptor (TCR), which often results in a weak tumor recognition efficiency. Our group has been focusing on the isolation of highly avid T cells against CT-antigens that are expressed in multiple myeloma, in particular MAGE-C1, MAGE-C2, and NY-ESO-1. The experimental approach was based on the stimulation of allo-restricted cytotoxic T cells, because highly avid T cells recognizing peptide epitopes in context with foreign HLA-alleles are not depleted in the thymus. HLA-A2-negative T cells were stimulated with HLA-A2-positive allogeneic dendritic cells that had been exogenously loaded with HLA-A2-binding peptides derived from NY-ESO-1, MAGE-C1 or MAGE-C2. Using this technique we were able to isolate allo-HLA-A2-restricted cytotoxic T lymphocyte (CTL) clones with peptide-dominant binding against known and novel peptide epitopes derived from NY-ESO-1, MAGE-C1 and MAGE-C2. The expanded peptide-specific CTL clones lysed HLA-A2-positive myeloma cell lines expressing NY-ESO-1, MAGE-C1 and MAGE-C2, respectively. Of note, the MAGE-C1-specific T cells crossreacted with the corresponding MAGE-C2 peptide due to the existing sequence homology between MAGE-C1 and MAGE-C2. Current experiments focus on redirecting primary T cells toward myeloma cells by retroviral gene transfer of CT-antigen-specific TCRs. The establishment of a set of high avidity TCRs specific for CT-antigens facilitates the development of adoptive transfer regimens based on TCR-transduced T cells for the treatment of multiple myeloma.

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