scholarly journals T cells discriminate between groups C1 and C2 HLA-C

2021 ◽  
Author(s):  
Malcolm J. W. Sim ◽  
Zachary Stotz ◽  
Jinghua Lu ◽  
Paul Brennan ◽  
Eric O. Long ◽  
...  
Keyword(s):  
T Cell ◽  
Killer Cell ◽  
Adoptive T Cell Therapy ◽  
Cell Recognition ◽  
T Cell Therapy ◽  
Cell Receptors ◽  
T Cell Recognition ◽  
Cell Responses ◽  
C Terminus ◽  
Peptide Presentation

Dimorphic residues at positions 77 and 80 delineate HLA-C allotypes into two groups, C1 and C2, which associate with disease through interactions with C1 and C2-specific natural killer cell receptors. How the C1/C2 dimorphism affects T cell recognition is unknown. Using HLA-C allotypes that differ only by the C1/C2-defining residues, we found that KRAS-G12D neoantigen specific T cell receptors (TCR) discriminated groups C1 and C2 HLA-C, due to effects on peptide presentation and TCR affinity. Structural and functional experiments combined with immunopeptidomics analysis revealed that C1-HLA-C favors smaller amino acids at the peptide C-terminus minus-1 position (pΩ-1), and that larger pΩ-1 residues diminished TCR recognition of C1-HLA-C. After controlling for peptide presentation, TCRs exhibited weaker affinities for C2-HLA-C despite conserved TCR contacts. Thus, the C1/C2 dimorphism impacts peptide presentation and HLA-C restricted T cell responses, with implications in multiple disease contexts including adoptive T cell therapy targeting KRAS-G12D-induced cancers.

Abstract 2564: Selection of affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10

2018 ◽  
Author(s):  
Ellen Border ◽  
Joseph P. Sanderson ◽  
Thomas Weissensteiner ◽  
Natalie Hyland ◽  
Tom Holdich ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
T Cell Receptors ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Cell Receptors ◽  
Selection Of

scholarly journals Affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10: strategy for selection of an optimal candidate

2018 ◽  
Vol 8 (2) ◽  
pp. e1532759 ◽  
Author(s):  
Ellen C. Border ◽  
Joseph P. Sanderson ◽  
Thomas Weissensteiner ◽  
Andrew B. Gerry ◽  
Nicholas J. Pumphrey
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
T Cell Receptors ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Cell Receptors ◽  
Optimal Candidate ◽  
Selection Of

Saccharomyces cerevisiae as delivery vehicle for a NY-ESO-1 protein vaccine

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2578-2578
Author(s):  
C. Renner ◽  
G. Held ◽  
F. Neumann ◽  
S. Kleber ◽  
M. Thiel ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
T Cell Responses ◽  
Full Length ◽  
Class I ◽  
Strong Positive Correlation ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Cross Presentation ◽  
Cell Responses

2578 Background: Vaccine strategies that target or activate dendritic cells in order to elicit potent cellular immunity are currently the subject of intense research. Here we report that genetically engineered yeast expressing the full-length tumor associated antigen NY-ESO-1 are a versatile host for protein production eliciting MHC class I and II T-cell responses. Methods: The pYD1 yeast display vector was chosen for full length NY-Eso-1 protein (pNY-ESO-1) expression. NY-ESO-1 and SSX-2 (as control) protein were affinity purified on. IFN-g ELISPOT assays were performed in triplicates on nitrocellulose-lined 96-well plates. MHC class I cross-presentation of peptide epitopes was demonstrated by blocking T-cell responses against DCs. For this purpose, antigen or peptide pulsed DCs were labeled with different doses (100, 10, 1 μg/ml) of antibodies specific for HLA-A2/peptide complexes (HLA-A2/ NY-Eso-1157–165; 3M4E5) or an irrelevant antibody (specific for HLA-A2/IMP58–66) as control. Results: Highest level of NY-ESO-1 expression was detected on the cell wall of wt EBY100 strain with lower expression levels on PMT deficient strains PMT-2 and PMT-4. After protein feeding of immature DCs, NY-ESO-1 157–165 peptide cross-presentation was detected by 3M4E5 and an antigen-specific CD8+ T cell clone. There was a strong positive correlation between the amount of Aga2p-NY-ESO-1 protein (0–15μg/ml) and peptide presentation. Specific T-cell recognition of NY-Eso-1 157–165/HLA-A2 complexes was validated by blocking experiments with Fab 3M4E5. Pre-incubation of protein fed DCs with the antibody at different concentrations (0–100 μg/ml) resulted in a significant reduction (p< 0.05) of spot numbers. Efficient presentation and T-cell recognition of epitope 157–165 was only adequately detectable when protein produced by EBY100 wt yeast strain was used (p < 0.05). MHC class II presentation was studied in an autologous setting using a T-cell line recognising the NY-ESO-1 157–170 in HLA-DP4 context revealing that NY-ESO-1 protein produced in yeast was efficiently taken up and presented. Conclusions: Together, these data add further evidence that yeast expressing recombinant proteins can be used for vaccine purposes and that antigen uptake in APC depends on glycoslation of yeast expressed antigens. No significant financial relationships to disclose.

scholarly journals T cell receptors for responses to Mls determinants and allo-H-2 determinants appear to be encoded on different chromosomes.

1985 ◽  
Vol 161 (1) ◽  
pp. 269-274 ◽  
Author(s):  
S R Webb ◽  
J H Li ◽  
I MacNeil ◽  
P Marrack ◽  
J Sprent ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
The Other ◽  
Cell Recognition ◽  
Dual Reactivity ◽  
T Cell Clones ◽  
Cell Receptors ◽  
T Cell Recognition ◽  
Cell Clones ◽  
Direct Support

Previous studies have shown that T cell clones specific for strong Mlsa,d determinants concomitantly display apparently random reactivity to allo-H-2 determinants. One explanation for this finding is that T cell recognition of Mlsa,d and allo-H-2 determinants is controlled by separate sets of receptors. If these receptors were chromosomally unlinked, karyotypically unstable T cell hybrids with dual reactivity for Mlsa,d and particular allo-H-2 determinants would be expected, occasionally, to lose reactivity for one set of determinants, but not the other. The results presented here provide direct support for this prediction.

scholarly journals CTLs respond with activation and granule secretion when serving as targets for T-cell recognition

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 1042-1052 ◽  
Author(s):  
Oren Milstein ◽  
David Hagin ◽  
Assaf Lask ◽  
Shlomit Reich-Zeliger ◽  
Elias Shezen ◽  
...  
Keyword(s):  
T Cell ◽  
Tolerance Induction ◽  
Cell Receptor ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Cell Responses ◽  
Single Cell Imaging ◽  
Histocompatibility Complex ◽  
Granule Secretion ◽  
Interfering Rna

Abstract Cytotoxic T lymphocytes (CTLs) suppress T cell responses directed against their antigens regardless of their own T cell receptor (TCR) specificity. This makes the use of CTLs promising for tolerance induction in autoimmunity and transplantation. It has been established that binding of the CTL CD8 molecule to the major histocompatibility complex (MHC) class I α3 domain of the recognizing T cell must be permitted for death of the latter cell to ensue. However, the signaling events triggered in the CTL by this molecular interaction in the absence of TCR recognition have never been clarified. Here we use single-cell imaging to study the events occurring in CTLs serving as targets for recognition by specific T cells. We demonstrate that CTLs actively respond to recognition by polarizing their cytotoxic granules to the contact area, releasing their lethal cargo, and vigorously proliferating. Using CTLs from perforin knockout (KO) mice and lymphocyte specific kinase (Lck) knockdown with specific small interfering RNA (siRNA), we show that the killing of the recognizing CD8 T cell is perforin dependent and is initiated by Lck signaling in the CTL. Collectively, these data suggest a novel mechanism in which the entire cascade generally triggered by TCR engagement is “hijacked” in CTLs serving as targets for T cell recognition without TCR ligation.

scholarly journals T-Cell Recognition of the HspX Protein of Mycobacterium tuberculosis Correlates with Latent M. tuberculosis Infection but Not with M. bovis BCG Vaccination

2007 ◽  
Vol 75 (6) ◽  
pp. 2914-2921 ◽  
Author(s):  
Annemieke Geluk ◽  
May Young Lin ◽  
Krista E. van Meijgaarden ◽  
Eliane M. S. Leyten ◽  
Kees L. M. C. Franken ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
T Cell Responses ◽  
Cell Recognition ◽  
T Cell Epitopes ◽  
Bcg Vaccination ◽  
T Cell Recognition ◽  
Cell Responses

ABSTRACT During stationary growth or in vitro conditions mimicking relevant aspects of latency, the HspX protein (Rv2031c) is specifically upregulated by Mycobacterium tuberculosis. In this study we compared T-cell responses against HspX and the secreted M. tuberculosis protein Ag85B (Rv1886c) in tuberculosis (TB) patients, tuberculin skin test-positive individuals, M. bovis BCG-vaccinated individuals, and healthy negative controls. Gamma interferon responses to HspX were significantly higher in M. tuberculosis-exposed individuals than in M. tuberculosis-unexposed BCG vaccinees. In contrast, no such differences were found with respect to T-cell responses against Ag85B. Therefore, BCG-based vaccines containing relevant fragments of HspX may induce improved responses against this TB latency antigen. To identify relevant major histocompatibility complex class I- and class II-restricted HspX-specific T-cell epitopes, we immunized HLA-A2/Kb and HLA-DR3.Ab0 transgenic (tg) mice with HspX. Two new T-cell epitopes were identified, p91-105 and p31-50, restricted via HLA-A*0201 and HLA-DRB1*0301, respectively. These epitopes were recognized by human T cells as well, underlining the relevance of HspX T-cell recognition both in vivo and in vitro. In line with the data in humans, BCG immunization of both tg strains did not lead to T-cell responses against HspX-derived epitopes, whereas nonlatency antigens were efficiently recognized. These data support the notion that BCG vaccination per se does not induce T-cell responses against the latency antigen, HspX. Thus, we suggest that subunit vaccines incorporating HspX and/or other latency antigens, as well as recombinant BCG strains expressing latency antigens need to be considered as new vaccines against TB.

scholarly journals Needle in a Haystack: The Naïve Repertoire as a Source of T Cell Receptors for Adoptive Therapy with Engineered T Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 8324 ◽  
Author(s):  
Elvira D’Ippolito ◽  
Karolin I. Wagner ◽  
Dirk H Busch
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Receptors ◽  
Adoptive T Cell Therapy ◽  
Patient Specific ◽  
Antigen Specificity ◽  
Adoptive Therapy ◽  
T Cell Therapy ◽  
Cell Receptors

T cell engineering with antigen-specific T cell receptors (TCRs) has allowed the generation of increasingly specific, reliable, and versatile T cell products with near-physiological features. However, a broad applicability of TCR-based therapies in cancer is still limited by the restricted number of TCRs, often also of suboptimal potency, available for clinical use. In addition, targeting of tumor neoantigens with TCR-engineered T cell therapy moves the field towards a highly personalized treatment, as tumor neoantigens derive from somatic mutations and are extremely patient-specific. Therefore, relevant TCRs have to be de novo identified for each patient and within a narrow time window. The naïve repertoire of healthy donors would represent a reliable source due to its huge diverse TCR repertoire, which theoretically entails T cells for any antigen specificity, including tumor neoantigens. As a challenge, antigen-specific naïve T cells are of extremely low frequency and mostly of low functionality, making the identification of highly functional TCRs finding a “needle in a haystack.” In this review, we present the technological advancements achieved in high-throughput mapping of patient-specific neoantigens and corresponding cognate TCRs and how these platforms can be used to interrogate the naïve repertoire for a fast and efficient identification of rare but therapeutically valuable TCRs for personalized adoptive T cell therapy.

Degenerate specificity of HTLV-1–specific CD8+ T cells during viral replication in patients with HTLV-1–associated myelopathy (HAM/TSP)

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3074-3081 ◽  
Author(s):  
Ryuji Kubota ◽  
Yoshitaka Furukawa ◽  
Shuji Izumo ◽  
Koichiro Usuku ◽  
Mitsuhiro Osame
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Cd8 T Cells ◽  
Proviral Load ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Cell Responses

AbstractHuman T-lymphotropic virus type 1 (HTLV-1)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurologic disease caused by HTLV-1 infection, in which HTLV-1–infected CD4+ T cells and HTLV-1–specific CD8+ T cells may play a role in the disease pathogenesis. Patients with HAM/TSP have high proviral loads despite vigorous virus-specific CD8+ T-cell responses; however, it is unknown whether the T cells are efficient in eliminating the virus in vivo. To define the dynamics of HTLV-1–specific CD8+T-cell responses, we investigated longitudinal alterations in HTLV-1 proviral load, amino acid changes in an immunodominant viral epitope, frequency of HTLV-1–specific T cells, and degeneracy of T-cell recognition in patients with HAM/TSP. We showed that the frequency and the degeneracy of the HTLV-1–specific CD8+ T cells correlated well with proviral load in the longitudinal study. The proviral load was much higher in a patient with low degeneracy of HTLV-1–specific T cells compared to that in a patient with comparable frequency but higher degeneracy of the T cells. Furthermore, in a larger number of patients divided into 2 groups by the proviral load, those with high proviral load had lower degeneracy of T-cell recognition than those with low proviral load. Sequencing analysis revealed that epitope mutations were remarkably increased in a patient when the frequency and the degeneracy were at the lowest. These data suggest that HTLV-1–specific CD8+ T cells with degenerate specificity are increased during viral replication and control the viral infection.

Sign in / Sign up

Export Citation Format

Share Document