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

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.

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

Communications Biology ◽

10.1038/s42003-021-02885-6 ◽

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.

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Cytotoxic T cell clone-specific monoclonal antibodies used to select clonotypic antigen-specific cytotoxic T cells

European Journal of Immunology ◽

10.1002/eji.1830150107 ◽

1985 ◽

Vol 15 (1) ◽

pp. 31-36 ◽

Cited By ~ 54

Author(s):

Hans Acha-Orbea ◽

Rolf M. Zinkernagel ◽

Hans Hengartner

Keyword(s):

T Cells ◽

Monoclonal Antibodies ◽

T Cell ◽

Cell Clone ◽

Cytotoxic T Cells ◽

Cytotoxic T Cell ◽

T Cell Clone

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Human Paramyxovirus Infections Induce T Cells That Cross-React with Zoonotic Henipaviruses

mBio ◽

10.1128/mbio.00972-20 ◽

2020 ◽

Vol 11 (4) ◽

Author(s):

Rory D. de Vries ◽

Alwin de Jong ◽

R. Joyce Verburgh ◽

Lucie Sauerhering ◽

Gijsbert P. van Nierop ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Measles Virus ◽

Cell Clone ◽

Cytotoxic T Cells ◽

Nipah Virus ◽

Cell Epitope ◽

Virus Infections ◽

Human T Cell ◽

T Cell Clone

ABSTRACT Humans are infected with paramyxoviruses of different genera early in life, which induce cytotoxic T cells that may recognize conserved epitopes. This raises the question of whether cross-reactive T cells induced by antecedent paramyxovirus infections provide partial protection against highly lethal zoonotic Nipah virus infections. By characterizing a measles virus-specific but paramyxovirus cross-reactive human T cell clone, we discovered a highly conserved HLA-B*1501-restricted T cell epitope in the fusion protein. Using peptides, tetramers, and single cell sorting, we isolated a parainfluenza virus-specific T cell clone from a healthy adult and showed that both clones cleared Nipah virus-infected cells. We identified multiple conserved hot spots in paramyxovirus proteomes that contain other potentially cross-reactive epitopes. Our data suggest that, depending on HLA haplotype and history of paramyxovirus exposures, humans may have cross-reactive T cells that provide protection against Nipah virus. The effect of preferential boosting of these cross-reactive epitopes needs to be further studied in light of paramyxovirus vaccination studies. IMPORTANCE Humans encounter multiple paramyxoviruses early in life. This study shows that infection with common paramyxoviruses can induce T cells cross-reactive with the highly pathogenic Nipah virus. This demonstrates that the combination of paramyxovirus infection history and HLA haplotype affects immunity to phylogenetically related zoonotic paramyxoviruses.

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The interaction between CD8+ cytotoxic T cells and Leishmania-infected macrophages.

Journal of Experimental Medicine ◽

10.1084/jem.174.3.499 ◽

1991 ◽

Vol 174 (3) ◽

pp. 499-505 ◽

Cited By ~ 44

Author(s):

L E Smith ◽

M Rodrigues ◽

D G Russell

Keyword(s):

T Cells ◽

T Cell ◽

Cell Clone ◽

Cytotoxic T Cells ◽

T Cell Response ◽

Cytotoxic T Cell ◽

T Cell Clone ◽

Vitro Model ◽

Leishmania Parasites

Leishmania is resident within the macrophages of its vertebrate host. In any intramacrophage infection, where the pathogen is present in a form capable of mediating cell to cell transmission, the contribution of a cytotoxic T cell response to protective immunity is questionable. This study presents data from an in vitro model designed to elucidate the outcome of an interaction between CD8+, cytotoxic T cells and infected macrophages. Experiments were conducted with an H-2d-restricted, cytotoxic CD8+ T cell clone and Leishmania parasites present in mixed macrophage cultures, with the parasites confined to either histocompatible BALB/c macrophages, or incompatible CBA macrophages. Initial experiments indicated that the viability of Leishmania was unaffected by the lysis of its host macrophage by cytotoxic T cells. However, extended experiments showed that the parasites were killed between 24 and 72 h. The same results were obtained regardless of whether the parasites were resident in the target, BALB/c, macrophages or the bystander, CBA, macrophages. Addition of neutralizing, anti-IFN-g antibody to the cultures ablated most of the leishmanicidal behavior, indicating that parasite death was attributable to macrophage activation, resulting from cytokine secretion from the T cells following the initial recognition event.

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Isolation of a T-Cell Clone Showing HLA-DRB1*0405-Restricted Cytotoxicity for Hematopoietic Cells in a Patient With Aplastic Anemia

Blood ◽

10.1182/blood.v89.10.3691 ◽

1997 ◽

Vol 89 (10) ◽

pp. 3691-3699 ◽

Cited By ~ 81

Author(s):

Shinji Nakao ◽

Akiyoshi Takami ◽

Hideyuki Takamatsu ◽

Weihua Zeng ◽

Naomi Sugimori ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Aplastic Anemia ◽

Mononuclear Cells ◽

Cell Clone ◽

Cytotoxic T Cells ◽

Hematopoietic Cells ◽

T Cell Clone ◽

Cd34 Cells

Abstract The existence of T cells capable of inhibiting in vitro hematopoiesis has been shown in aplastic anemia (AA), although whether such inhibition is mediated by a specific immune reaction involving an HLA allele remained unknown. We isolated a CD4+ Vβ21+ T-cell clone that was most dominant among Vβ21+ T cells in the bone marrow (BM) of an AA patient whose HLA-DRB1 alleles included 1501 and 0405. The T-cell clone named NT4.2 lysed an autologous Epstein-Barr virus-transformed lymphoblastoid cell line (LCL) and phytohemagglutinin-stimulated lymphocytes (PHA-blasts) as well as allogeneic LCLs sharing HLA-DRB1*0405. Cytotoxicity against LCL cells and PHA-blasts by NT4.2 was blocked by anti–HLA-DR monoclonal antibody (MoAb) or anti-CD3 MoAb. NT4.2 also lysed autologous BM mononuclear cells enriched with CD34+ cells that had been cultured for one week in the presence of colony-stimulating factors as well as allogeneic CD34+ cells of a normal individual carrying HLA-DRB1*0405, cultured in the same way. Moreover, NT4.2 strongly inhibited colony formation by hematopoietic progenitor cells derived from cultured CD34+ cells sharing HLA-DRB1*0405. These results indicate that the AA patient has T cells capable of killing hematopoietic cells in an HLA-DRB1*0405-restricted manner and that such cytotoxic T cells may contribute to the pathogenesis of AA.

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Isolation of a T-Cell Clone Showing HLA-DRB1*0405-Restricted Cytotoxicity for Hematopoietic Cells in a Patient With Aplastic Anemia

Blood ◽

10.1182/blood.v89.10.3691.3691_3691_3699 ◽

1997 ◽

Vol 89 (10) ◽

pp. 3691-3699 ◽

Cited By ~ 1

Author(s):

Shinji Nakao ◽

Akiyoshi Takami ◽

Hideyuki Takamatsu ◽

Weihua Zeng ◽

Naomi Sugimori ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Aplastic Anemia ◽

Mononuclear Cells ◽

Cell Clone ◽

Cytotoxic T Cells ◽

Hematopoietic Cells ◽

T Cell Clone ◽

Cd34 Cells

The existence of T cells capable of inhibiting in vitro hematopoiesis has been shown in aplastic anemia (AA), although whether such inhibition is mediated by a specific immune reaction involving an HLA allele remained unknown. We isolated a CD4+ Vβ21+ T-cell clone that was most dominant among Vβ21+ T cells in the bone marrow (BM) of an AA patient whose HLA-DRB1 alleles included 1501 and 0405. The T-cell clone named NT4.2 lysed an autologous Epstein-Barr virus-transformed lymphoblastoid cell line (LCL) and phytohemagglutinin-stimulated lymphocytes (PHA-blasts) as well as allogeneic LCLs sharing HLA-DRB1*0405. Cytotoxicity against LCL cells and PHA-blasts by NT4.2 was blocked by anti–HLA-DR monoclonal antibody (MoAb) or anti-CD3 MoAb. NT4.2 also lysed autologous BM mononuclear cells enriched with CD34+ cells that had been cultured for one week in the presence of colony-stimulating factors as well as allogeneic CD34+ cells of a normal individual carrying HLA-DRB1*0405, cultured in the same way. Moreover, NT4.2 strongly inhibited colony formation by hematopoietic progenitor cells derived from cultured CD34+ cells sharing HLA-DRB1*0405. These results indicate that the AA patient has T cells capable of killing hematopoietic cells in an HLA-DRB1*0405-restricted manner and that such cytotoxic T cells may contribute to the pathogenesis of AA.

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CD8 T cells are not required for islet destruction induced by a CD4+ islet-specific T-cell clone

Diabetes ◽

10.2337/diabetes.41.12.1603 ◽

1992 ◽

Vol 41 (12) ◽

pp. 1603-1608 ◽

Cited By ~ 20

Author(s):

B. J. Bradley ◽

K. Haskins ◽

F. G. La Rosa ◽

K. J. Lafferty

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Clone ◽

T Cell Clone

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

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5115 ◽

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

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