scholarly journals Identification of TCR repertoires in functionally competent cytotoxic T cells cross-reactive to SARS-CoV-2

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Kanako Shimizu ◽  
Tomonori Iyoda ◽  
An Sanpei ◽  
Hiroshi Nakazato ◽  
Masahiro Okada ◽  
...  
Keyword(s):  
T Cells ◽  
Hematological Malignancy ◽  
Cytotoxic T Cells ◽  
Cross Reactivity ◽  
Cell Level ◽  
Human Coronavirus ◽  
Healthy Donors ◽  
Selective Diversity ◽  
Dominant Epitope ◽  
Immunodominant Epitopes

AbstractSARS-CoV-2-specific CD8+ T cells are scarce but detectable in unexposed healthy donors (UHDs). It remains unclear whether pre-existing human coronavirus (HCoV)-specific CD8+ T cells are converted to functionally competent T cells cross-reactive to SARS-CoV-2. Here, we identified the HLA-A24-high binding, immunodominant epitopes in SARS-CoV-2 spike region that can be recognized by seasonal coronavirus-specific CD8+ T cells from HLA-A24+ UHDs. Cross-reactive CD8+ T cells were clearly reduced in patients with hematological malignancy, who are usually immunosuppressed, compared to those in UHDs. Furthermore, we showed that CD8+ T cells in response to a selected dominant epitope display multifunctionality and cross-functionality across HCoVs in HLA-A24+ donors. Cross-reactivity of T-cell receptors isolated from them exhibited selective diversity at the single-cell level. Taken together, when stimulated well by immunodominant epitopes, selective pre-existing CD8+ T cells with high functional avidity may be cross-reactive against SARS-CoV-2.

scholarly journals Identification of TCR repertoires in functionally competent cytotoxic T cells cross-reactive to SARS-CoV-2

2021 ◽  
Author(s):  
Kanako Shimizu ◽  
Tomonori Iyoda ◽  
An Sanpei ◽  
Hiroshi Nakazato ◽  
Masahiro Okada ◽  
...  
Keyword(s):  
T Cells ◽  
Vaccine Development ◽  
Cell Clone ◽  
Cytotoxic T Cells ◽  
Cell Level ◽  
Human Coronavirus ◽  
Healthy Donors ◽  
T Cell Clone ◽  
Selective Diversity ◽  
Dominant Epitope

Abstract SARS-CoV-2-specific CD8+ T cells are detectable in infected individuals but are low in unexposed healthy donors (UHD). Little is known about whether pre-existing human coronavirus (HCoV)-specific CD8+ T cells are converted to functionally competent T cells cross-reactive to SARS-CoV-2. Induction of cross-reactive immunity requires the recognition of multiple epitopes. Here, we show that SARS-CoV-2-specific T cells elicited in response to a selected dominant epitope are multifunctional and respond to various HCoVs in UHD. TCRαβ chains from each T cell clone were identified; TCRαβ-transduced T cells responded broadly to the relevant epitopes on several HCoVs, thus implying that TCRαβ may exhibit selective diversity at the single-cell level. We further defined four sets of optimal SARS-CoV-2-peptides and demonstrated the response of CD8+ T cells even in hematological malignant patients. Together, the proposed epitopes inducing pre-existing CD8+ T cells to cross-react with SARS-CoV-2 may be beneficial in vaccine development.

scholarly journals AB0084 TNF RECEPTORS PROFILE CHANGES ON CYTOTOXIC T CELLS SUBSETS IN RHEUMATOID ARTHRITIS ARE ASSOCIATED WITH EFFECTIVE TREATMENT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1341.3-1342
Author(s):  
A. Alshevskaya ◽  
J. Lopatnikova ◽  
J. Zhukova ◽  
F. Kireev ◽  
O. Chumasova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Effective Treatment ◽  
Expression Profile ◽  
Cytotoxic T Cells ◽  
Activity Level ◽  
Receptor Expression ◽  
Healthy Donors ◽  
Therapy Effect

Background:Previous studies of co-expression profile of receptors to tumor necrosis factor alpha (TNF) in rheumatoid arthritis (RA) have revealed a number of indicators associated with diseases activity with 93% sensitivity and 90% specificity. However, the ratio of receptors to cytokines remains poorly understood. However, the question of therapy effect and its effectiveness in various alteration of cytokine receptors balance remains under investigated.Objectives:To evaluate the dynamics of co-expression and quantitative expression of type 1 and 2 receptors for TNF in the subpopulations of CD3+CD8+ cells associated with changes in disease severity before and after effective basic therapy.Methods:Subanalysis of patients with high disease activity level successfully treated with methotrexate and oral glucocorticoids (n = 9) was performed. As a control group, we used data from 43 healthy donors, comparable by sex and age distribution. Subpopulations of cytotoxic T cells were studied, which were included in the final diagnostic models for differentiating different degrees of severity of RA: naive T cells and memory T cells. The dynamics of changes in the indicators of receptors number and proportion of cells expressing the corresponding receptor were compared.Results:For naïve cytotoxic T cells, the main revealed feature was the relative stability of the number of expressed receptors (both TNFR1 and TNFR2), regardless of the therapy, while this number did not significantly differ from healthy ones for TNFR1 and was significantly lower for TNFR2 (p <0.05 for all three fractions). At the same time, in terms of cell percentage, on the contrary, the therapy led to a change in total proportion of TNFR1 + cells closer to healthy donors indicators, and the proportion of TNFR2 + cells in the opposite direction.For cytotoxic T memory cells, it was demonstrated that after successful treatment a significant increase in the number of type 1 receptors was observed, with a decrease in TNFR1+ cells proportion, while these indicators were close to the values of healthy donors. At the same time, healthy donors were characterized by a significantly higher expression of type 2 receptors in terms of cell density of receptors. It is noteworthy that with successful therapy, a slight increase in the number of TNFR2 was observed with a sharp decrease in the proportion of TNFR2+ cells (p = 0.043).Conclusion:The balance of TNF receptor expression on cells actively involved in immunopathological processes affects both the density distribution of receptors on cells and co-expression in a subpopulation. Effective treatment of RA leads to equalization of the expression profile either by the percentage of cells or by the number of receptors, approaching the indicators of healthy donors, but not simultaneously.Disclosure of Interests:None declared

scholarly journals Cytotoxic T cells isolated from healthy donors and cancer patients kill TGFβ-expressing cancer cells in a TGFβ-dependent manner

2021 ◽  
Author(s):  
Morten Orebo Holmström ◽  
Rasmus Erik Johansson Mortensen ◽  
Angelos Michail Pavlidis ◽  
Evelina Martinenaite ◽  
Stine Emilie Weis-Banke ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cytotoxic T Cells ◽  
Dependent Manner ◽  
Healthy Donors

Viral Cross-Reactivity and Antigenic Determinants Recognized by Human Parainfluenza Virus Type 1-Specific Cytotoxic T-Cells

Virology ◽  
1994 ◽  
Vol 199 (2) ◽  
pp. 376-383 ◽  
Author(s):  
Vibhuti P. Dave ◽  
Jane E. Allan ◽  
Karen S. Slobod ◽  
F.Suzette Smith ◽  
Kevin W. Ryan ◽  
...  
Keyword(s):  
T Cells ◽  
Virus Type ◽  
Cytotoxic T Cells ◽  
Cross Reactivity ◽  
Parainfluenza Virus ◽  
Antigenic Determinants ◽  
Human Parainfluenza Virus

The shared tumor-associated antigen cytochrome P450 1B1 is recognized by specific cytotoxic T cells

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3287-3294 ◽  
Author(s):  
Britta Maecker ◽  
David H. Sherr ◽  
Robert H. Vonderheide ◽  
Michael S. von Bergwelt-Baildon ◽  
Naoto Hirano ◽  
...  
Keyword(s):  
T Cells ◽  
Cytochrome P450 ◽  
Cytotoxic T Cells ◽  
Phase 1 ◽  
Cell Epitope ◽  
Target Cells ◽  
Cytochrome P450 1B1 ◽  
Tumor Associated Antigen ◽  
Healthy Donors ◽  
Binding Peptides

AbstractCytochrome P450 1B1 (CYP1B1), a drug-metabolizing extrahepatic enzyme, was recently shown to be overexpressed in multiple types of cancer. Such tumor-associated genes may be useful targets for anticancer therapy, particularly cancer immunotherapeutics. We identified HLA-A*0201–binding peptides and a naturally processed and presented T-cell epitope capable of inducing CYP1B1-specific cytotoxic T lymphocytes (CTLs) in HLA-A2 transgenic mice. Furthermore, the induction of CYP1B1-specific T cells was demonstrated in healthy donors and cancer patients. These T cells efficiently lysed target cells pulsed with the cognate peptide. More important, HLA-A2–matched tumor cell lines and primary malignant cells were also recognized by CYP1B1-specific CTLs. These findings form the basis of a phase 1 clinical trial exploring a DNA-based vector encoding CYP1B1 for widely applicable cancer immunotherapy conducted at the Dana-Farber Cancer Institute.

scholarly journals Specificity of cytotoxicity T cells directed to influenza virus hemagglutinin.

1979 ◽  
Vol 149 (4) ◽  
pp. 856-869 ◽  
Author(s):  
T J Braciale
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Type A ◽  
Cross Reactivity ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Effector Cells ◽  
Cell Induction

Purified type A influenza viral hemagglutinin stimulates an in vitro cell-mediated cytotoxic cell response that exhibits a high degree of specificity for the immunizing hemagglutinin. The response magnitude is proportional to the hemagglutinin dose used for stimulation. The lytic activity of the effector cells is H-2 restricted. Analysis of the specificity of the response indicated that these cytotoxic T cells readily distinguish target cells expressing serologically unrelated hemagglutinin from target cells bearing hemagglutinins serologically related to the stimulating hemagglutinin. Further analysis of the fine specificity of cytotoxic T-cell recognition with serologically cross-reactive type A influenza hemagglutinins revealed a hierarchy of cross-reactivity among these hemagglutinins that was the converse of the serologic hierarchy. These results are discussed in terms of possible differences and similarities in the specificity repertoire of cytotoxic T cells and antibodies. Possible implications of these findings from the standpoint of cytotoxic T-cell induction are also discussed.

scholarly journals Repertoire of Cytomegalovirus-Specific T Cells Is Focused on the Immunodominant Epitopes in Fixed Hierarchy Dependent on HLA Genotype of the Donor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2327-2327
Author(s):  
Alexandra Vladimirovna Maleeva ◽  
Vyacheslav Anatolevich Shmarov ◽  
Dmitry Olegovych Kiryukhin ◽  
Grigory Aleksandrovich Efimov ◽  
Valery G. Savchenko
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Specific Cell ◽  
Specific Response ◽  
Intracellular Staining ◽  
Hematopoietic Stem ◽  
Healthy Donors ◽  
Immunodominant Antigens ◽  
Immunodominant Epitopes

Background: Cytomegalovirus (HCMV) infection is one of the major complications and causes of mortality in patients receiving immunosuppressive therapy following hematopoietic stem cell transplantation (HSCT). Antiviral drugs have limited efficacy and high toxicity while using CMV-specific T cells from healthy individuals as a cellular vaccine had proven to be safe and efficient. Conventional protocols rely on expanding virus-specific cells ex vivo while more recently it was proposed to transfuse relatively small numbers of minimally manipulated cells and allow them to expand in vivo. To isolate virus-specific cell one could use either the stimulation with overlapping pools of peptides covering the whole immunogenic viral protein followed by isolation of INFγ-producing cells, or direct isolations of cells bound to MHC-multimer loaded with known immunodominant peptides. Both methods have their advantages. The former approach isolates all activated clones irrespective of their MHC-restriction and supplements CD8+ cells with CD4+ fraction, while the latter method is faster and simpler, besides it captures cells irrespective of their ability to produce IFNγ. The efficiency of the two methods was not directly compared and it is currently unknown to what extent T-cell populations isolated by these two approaches are different in terms of absolute quantity and clonal composition. Aims: to compare the quantity and T-cell receptor repertoire composition of T cells specific to pp65 CMV and to pp65-derived immunodominant epitopes NLV restricted by HLA-A*02, TPR and RPH restricted both by HLA-B*07. Methods: PBMC of healthy donors with different combination of HLA-A*02 and HLA-B*07 alleles were stimulated with peptides of immunodominant epitopes or overlapping peptide pool covering the entire pp65 CMV (Miltenyi Biotec, Cat.-130-093-435). Antigen-specific T cells were detected by the intracellular staining for IFNγ and flow cytometry. We obtained fractions of virus-specific T cells from PBMC either by MHC-tetramer staining or IFNγ secretion assay followed by fluorescent activated cell sorting. Then we prepared cDNA libraries of TCR α- and β-chains and sequenced them using NGS. Characterization of TCR repertories was performed by proprietary bioinformatic pipeline. Results: T-cell response to pp65 CMV is strongly focused on immunodominant pp65-derived epitopes. In donors having HLA-A*02 and/or HLA-B*07 absolute majority of pp65-reactive cells are specific to one of the three immunodominant epitopes - NLV, TPR and RPH. Immunodominant antigens are structured in a fixed hierarchy. TPR and RPH are superior to NLV. When HLA-B*07 is present response to the NLV epitope is drastically reduced, most of the pp65-specific cells recognize either TPR or RPH epitopes. TCR repertoire of the NLV-specific T cells is highly skewed and consists of few large dominant clones. TPR and RPH-specific T cells are more clonally diverse. Substantial share of the cells belonging to the large clones specific to the immunodominant antigens do not secrete IFNγ upon antigenic stimulation. Nevertheless, they may be therapeutically valuable, as they might secrete other cytokines. Conclusion: In summary, CMV-specific response in donors positive for HLA-A*02 and/or HLA-B*07 is focused to the combination of three immunodominant epitopes - NLV, TPR and RPH. Substantial share of the cells are not IFNγ-producers. For the patients having these alleles it might be beneficial to use MHC-multimers for isolation of the therapeutic lymphocytes. Figure 1: A - Healthy donors with different combination of HLA-A*02 and HLA-B*07 B - Intracellular staining for IFNγ of CD8+ T cells after stimulation with pp65-derived peptides C - NGS to identify clonally diverse of pp65-sprcific T cells on combination of HLA-A*02 and HLA-B*07 Figure 1 Disclosures No relevant conflicts of interest to declare.

CD137/4-1BB Is Inducibly Expressed On CLL B Cells through CD40 Signaling.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1266-1266
Author(s):  
Tetsuya Fukuda ◽  
Yukana Nakaima ◽  
Aya Kasubata ◽  
Ken Watanabe ◽  
Takatoshi Koyama ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nuclear Translocation ◽  
Conflicts Of Interest ◽  
Cytotoxic T Cells ◽  
Cd40 Ligation ◽  
Activated T Cells ◽  
Blocking Antibody ◽  
Healthy Donors

Abstract Abstract 1266 Poster Board I-288 CD137/4-1BB, a TNFR family member is expressed on activated T cells as a co-stimulator. It transduces the signal for cell survival and differentiation and plays a crucial role in CD8 cytotoxic T cells. Recently, an increasing number of reports have indicated its important role on tumor immunity, and the studies of immunotherapy targeting CD137 are on going. Therefore, it is important to know the expression of CD137 and CD137L on malignant cells for the establishment of immunotherapy. As a first step, we examined CD137 expression on PBMCs from healthy donors and CLL patients. When PBMCs from healthy donors were stimulated with PMA and ionomycin, CD137 expression was induced not only on T cells but also on activated B cells. However, when PBMCs from CLL patients were stimulated in the same way, we could not detect CD137 induction on CLL B cells. Since more than 90% of lymphocytes in the patients were CLL B cells, it is conceivable that activated T cells were required to induce CD137 on B cells. To test this hypothesis we next co-cultured CLL cells with T cells activated with anti-CD3/CD28 antibody-coated beads. In this co-culture CD137 was induced on CLL B cells, and this induction was diminished by anti-CD154 blocking antibody. Furthermore, CD137 was inducibly expressed on CLL B cells after co-culture with HeLa cells transfected with CD154 gene. The induction of CD137 mRNA was also clearly detected by RT-PCR after this stimulation. This CD137 induction was more significantly observed on CLL B cells (n=14, MFIR 11.5±6.9) as compared with B cells from healthy donors (n=4, MFIR 3.7±0.6, p=0.001) or non-CLL B cell malignancies (n=9, MFIR 4.2±3.43, p=0.003). Stimulation of CD137 expressed on BJAB transfectants by co-culture with CD137L-transfected CHO cells induced a conspicuous nuclear translocation of p52, a non-canonical NF-κB factor. In agreement with this activation, the expression of survival factor BCL-XL was upregulated. Consequently, the CD137 signal augmented the survival of CD154 stimulated CLL B cells in vitro. CD40 ligation can induce anti-CLL immunity and reduce CLL cells clinically. These data suggest that the inducibly expressed CD137 may diminish the effectiveness. It is possible that the fine adjustment of these co-stimulators can lead more effective immunotherapy. Disclosures No relevant conflicts of interest to declare.

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