scholarly journals The Single Positive T Cells Found in CD3-ζ/η−/− Mice Overtly React with Self–Major Histocompatibility Complex Molecules upon Restoration of Normal Surface Density of T Cell Receptor–CD3 Complex

1997 ◽  
Vol 185 (4) ◽  
pp. 707-716 ◽  
Author(s):  
Shih-Yao Lin ◽  
Laurence Ardouin ◽  
Anne Gillet ◽  
Marie Malissen ◽  
Bernard Malissen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
Normal Density ◽  
Cell Receptors ◽  
Peripheral T Cells ◽  
Single Positive ◽  
Deficient Mice

CD3-ζ/η–deficient mice have small thymuses containing cells that show a profound reduction in the surface levels of T cell receptors and terminate their differentiation at the CD4+CD8+ stage. Rather unexpectedly, CD3− or very low single positive T cells accumulate over time in the spleen and lymph nodes of CD3-ζ/η–deficient mice after a process dependent on MHC expression. Fusion of these peripheral T cells with a CD3-ζ–positive derivative of the BW5147 TCR-α−/β− thymoma resulted in hybridomas that do express an heterogeneous set of T cell receptor α/β dimers at their surface and at density comparable to those found in hybridomas derived from wild-type peripheral T cells. We have investigated the specificities of these T cell receptors using spleen cells from congenic and mutant mouse strains, and showed that the majority of them readily recognized self-MHC class I or class II molecules. These results demonstrate that by increasing the density and/or output of the T cell receptors expressed in peripheral T cells, one can confer them with the capacity to respond to normal density of self-MHC molecules.

scholarly journals T Cell Receptor Transfection Shows Non-HLA-Restricted Recognition of Nickel by CD8+ Human T Cells to be Mediated by αβ T Cell Receptors

2003 ◽  
Vol 121 (3) ◽  
pp. 496-501 ◽  
Author(s):  
Corinne Moulon ◽  
Yoanna Choleva ◽  
Hermann-Josef Thierse ◽  
Doris Wild ◽  
Hans Ulrich Weltzien
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
Cell Receptors ◽  
Human T Cells

scholarly journals Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes.

1996 ◽  
Vol 183 (3) ◽  
pp. 1053-1062 ◽  
Author(s):  
N S van Oers ◽  
N Killeen ◽  
A Weiss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Phosphorylation ◽  
T Cell Receptor ◽  
Tyrosine Kinases ◽  
Cell Receptor ◽  
Protein Tyrosine Kinases ◽  
Peripheral T Cells ◽  
Tcr Signal Transduction ◽  
Deficient Mice

The Src-family and Syk/ZAP-70 family of protein tyrosine kinases (PTK) are required for T cell receptor (TCR) functions. We provide evidence that the Src-family PTK Lck is responsible for regulating the constitutive tyrosine phosphorylation of the TCR zeta subunit in murine thymocytes. Moreover, ligation of the TCR expressed on thymocytes from Lck-deficient mice largely failed to induce the phosphorylation of TCR-zeta, CD3 epsilon, or ZAP-70. In contrast, we find that the TCR-zeta subunit is weakly constitutively tyrosine phosphorylated in peripheral T cells isolated from Lck-null mice. These data suggest that Lck has a functional role in regulation of TCR signal transduction in thymocytes. In peripheral T cells, other Src-family PTKs such as Fyn may partially compensate for the absence of Lck.

scholarly journals Immunopeptidomics and Peptide Expression Profiles to Develop T-Cell Receptors Against Glioma-Associated Antigens

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Diego A Carrera ◽  
Josie Hayes ◽  
Sören Müller ◽  
Payal Watchmaker ◽  
Samuel Shelton ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
Low Grade ◽  
Normal Brain ◽  
Who Grade ◽  
Cell Receptors ◽  
Normal Tissues

Abstract INTRODUCTION Diffuse infiltrating low-grade gliomas (WHO grade II and III) are slow-growing primary brain tumors, but considered malignant due to their invasive growth and inexorable malignant progression at recurrence. Highly personalized immunotherapies are currently a challenging endeavor, due to the low mutational load of gliomas, as described by various neoantigen discovery pipelines. Hence, it is important to extend our antigen search to other gene alterations such as alternative splicing or target epitopes derived from proteins that are absent in normal tissues. The purpose of this study is to address this gap and increase the available repertoire of T-cell receptors to target in gliomas. METHODS In the current study, we start by analyzing a set of 64 peptides derived from nonmutated proteins reported by Hilf et al (Nature, 2019) as part of their actively personalized vaccination trial. These were isolated from the human leukocyte antigen (HLA)-A*02:01 and A*24:02 molecules of primary glioblastoma tissues. The initial screening for immunogenic targets was performed assessing datasets of RNA expression levels in normal brain and peripheral organs and measure the differential expression in primary gliomas paired with their corresponding recurrent tumors. RESULTS We find 3 antigen epitopes being exclusively expressed in gliomas that increase their expression at recurrence, without significant levels in normal tissues. Furthermore, we report an epitope derived from a tumor-specific isoform, which we use to stimulate healthy-donor PBMCs and isolate reactive CD8+ T-cells to sequence their T-cell receptor and engineer patient-derived T-cells against this target. CONCLUSION Our results suggest that cell-based immunotherapies targeting these epitopes can be highly effective and safe, reducing the likelihood of adverse events, effectively addressing tumor heterogeneity and interpatient variability. Moreover, this is the first successful attempt to target an epitope derived from a tumor-specific isoform in glioma with an engineered T-cell receptor.

Functional double-negative T cells in the periphery express T cell receptor Vβ gene products that cause deletion of single-positive T cells

1993 ◽  
Vol 23 (1) ◽  
pp. 250-254 ◽  
Author(s):  
Carlos Martínez-a ◽  
Miguel A. R. Marcos ◽  
Ignacio M. de Alboran ◽  
José María Alonso ◽  
Rafael de Cid ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Double Negative ◽  
Gene Products ◽  
Single Positive ◽  
Double Negative T Cells ◽  
T Cell Receptor Vβ

Functional and Molecular Analysis of Maturation of Thymocytes in Bcl10 or Malt1 Deficient Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3323-3323
Author(s):  
Philipp J. Jost ◽  
Uta Ferch ◽  
Stephanie Weiss ◽  
Stephanie Leeder ◽  
Olaf Gross ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Animals ◽  
Adaptor Proteins ◽  
Cell Receptor ◽  
Single Positive ◽  
T Cell Selection ◽  
Deficient Mice

Abstract Development of immature T cells in the thymus requires signals through the clonotypic T cell receptor (TCR). Thymocytes expressing a functionally inactive or autoreactive TCR are deleted via apoptosis (negative selection). Thymocytes expressing a functionally active but not autoreactive TCR are selected through inhibition of cell death (positive selection). Deregulation of this process is likely to result in autoimmunity or lymphomagenesis of T cells. The intracellular mechanisms by which the balance between TCR-dependent survival and apoptosis are regulated are largely unknown. A central regulator of survival and apoptosis in the immune system is the transcription factor NF-κB. Activation of NF-κB in mature T-cells requires the adaptor proteins Bcl10 and Malt1. Using gene-targeted mice deficient for Bcl10 or Malt1, we show that Bcl10 and Malt1 are also required for TCR-induced NF-κB activation in immature T cells. Furthermore, to elucidate the process of T cell selection within the thymus, we have crossed Bcl10 or Malt1 deficient mice into mice with genetic backgrounds expressing defined TCR transgenes. Using specific peptide agonists of these TCR transgenes, we show that neither in vivo nor in vitro development into single positive (SP) CD4 or CD8 positive T cells is altered in Bcl10 or Malt1 deficient mice. Absolute numbers and ratio of SP T cells found within the thymus or in peripheral lymphnodes of transgenic animals are normal. These findings indicate that Bcl10 and Malt1 activate NF-κB in thymocytes but are dispensable for maturation of immature T cells in this model system.

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 Pre–T Cell Receptor (Tcr) and Tcr-Controlled Checkpoints in T Cell Differentiation Are Set by Ikaros

1999 ◽  
Vol 190 (8) ◽  
pp. 1039-1048 ◽  
Author(s):  
Susan Winandy ◽  
Li Wu ◽  
Jin-Hong Wang ◽  
Katia Georgopoulos
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Differentiation ◽  
Tcr Signaling ◽  
Double Positive ◽  
Single Positive ◽  
T Cell Malignancies ◽  
Deficient Mice

T cell differentiation relies on pre–T cell receptor (TCR) and TCR signaling events that take place at successive steps of the pathway. Here, we show that two of these T cell differentiation checkpoints are regulated by Ikaros. In the absence of Ikaros, double negative thymocytes can differentiate to the double positive stage without expression of a pre-TCR complex. Subsequent events in T cell development mediated by TCR involving transition from the double positive to the single positive stage are also regulated by Ikaros. Nonetheless, in Ikaros-deficient thymocytes, the requirement of pre-TCR expression for expansion of immature thymocytes as they progress to the double positive stage is still maintained, and the T cell malignancies that invariably arise in the thymus of Ikaros-deficient mice are dependent on either pre-TCR or TCR signaling. We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR.

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