SARS‐CoV‐2 spike glycoprotein‐reactive T cells can be readily expanded from COVID‐19 vaccinated donors

The adaptive immune response to severe acute respiratory coronavirus 2 (SARS-CoV-2) is important for vaccine development and in the recovery from coronavirus disease 2019 (COVID-19). Men and cancer patients have been reported to be at higher risks of contracting the virus and developing the more severe forms of COVID-19. Prostate cancer (PCa) may be associated with both of these risks. We show that CD4+ T cells of SARS-CoV-2-unexposed patients with hormone-refractory (HR) metastatic PCa had decreased CD4+ T cell immune responses to antigens from SARS-CoV-2 spike glycoprotein but not from the spiked glycoprotein of the ‘common cold’-associated human coronavirus 229E (HCoV-229E) as compared with healthy male volunteers who responded comparably to both HCoV-229E- and SARS-CoV-2-derived antigens. Moreover, the HCoV-229E spike glycoprotein antigen-elicited CD4+ T cell immune responses cross-reacted with the SARS-CoV-2 spiked glycoprotein antigens. PCa patients may have impaired responses to the vaccination, and the cross-reactivity can mediate antibody-dependent enhancement (ADE) of COVID-19. These findings highlight the potential for increased vulnerability of PCa patients to COVID-19.

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Presence of SARS-CoV-2-reactive T cells in COVID-19 patients and healthy donors

10.1101/2020.04.17.20061440 ◽

2020 ◽

Cited By ~ 57

Author(s):

Julian Braun ◽

Lucie Loyal ◽

Marco Frentsch ◽

Daniel Wendisch ◽

Philipp Georg ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Transmembrane Domain ◽

Clinical Manifestations ◽

T Cell Responses ◽

Spike Glycoprotein ◽

Cell Responses ◽

Healthy Donors

SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a rapidly unfolding pandemic, overwhelming health care systems worldwide1. Clinical manifestations of Coronavirus-disease 2019 (COVID-19) vary broadly, ranging from asymptomatic infection to acute respiratory failure and death2, yet the underlying mechanisms for this high variability are still unknown. Similarly, the role of host immune responses in viral clearance of COVID-19 remains unresolved. For SARS-CoV (2002/03), however, it has been reported that CD4+ T cell responses correlated with positive outcomes3,4, whereas T cell immune responses to SARS-CoV-2 have not yet been characterized. Here, we describe an assay that allows direct detection and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood. We demonstrate the presence of S-reactive CD4+ T cells in 83% of COVID-19 patients, as well as in 34% of SARS-CoV-2 seronegative healthy donors (HD), albeit at lower frequencies. Strikingly, S-reactive CD4+ T cells in COVID-19 patients equally targeted N-terminal and C-terminal epitopes of S whereas in HD S-reactive CD4+ T cells reacted almost exclusively to the C-terminal epitopes that are a) characterized by higher homology with spike glycoprotein of human endemic “common cold” coronaviruses (hCoVs), and b) contains the S2 subunit of S with the cytoplasmic peptide (CP), the fusion peptide (FP), and the transmembrane domain (TM) but not the receptor-binding domain (RBD). In contrast to S-reactive CD4+ T cells in HD, S-reactive CD4+ T cells from COVID-19 patients co-expressed CD38 and HLA-DR, indivative of their recent in vivo activation. Our study is the first to directly measure SARS-CoV-2-reactive T cell responses providing critical tools for large scale testing and characterization of potential cross-reactive cellular immunity to SARS-CoV-2. The presence of pre-existing SARS-CoV-2-reactive T cells in a subset of SARS-CoV-2 naïve HD is of high interest but larger scale prospective cohort studies are needed to assess whether their presence is a correlate of protection or pathology for COVID-19. Results of such studies will be key for a mechanistic understanding of the SARS-CoV-2 pandemic, adaptation of containment methods and to support vaccine development.

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Dose-Related Aberrant Inhibition of Intracellular Perforin Expression by S1 Subunit of Spike Glycoprotein That Contains Receptor-Binding Domain from SARS-CoV-2

Microorganisms ◽

10.3390/microorganisms9061303 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1303

Author(s):

Chun-Fu Huang ◽

Szu-Min Hsieh ◽

Sung-Ching Pan ◽

Yu-Shang Huang ◽

Shan-Chwen Chang

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cell Model ◽

Interferon Γ ◽

Negative Slope ◽

High Dose ◽

Cytotoxic Lymphocytes ◽

Dependent Manner ◽

Spike Glycoprotein ◽

Perforin Expression

Studies had shown that severe cases of COVID-19 tend to have high viral loads and correlate with functional impairment of cytotoxic lymphocytes, and the features of cytokine storm syndrome are similar to manifestations of severe influenza that have been partially explained by suppressed perforin expression. To test the hypothesis that the spike glycoprotein from SARS-CoV-2 may inhibit the perforin expression, we determined the kinetics of immune responses of CD8+ T cells to low dose (LD) or high dose (HD) of S1 stimulation through an in vitro dendritic cell (DC)-T cell model over seven days of incubation. The cytotoxic activity and intracellular perforin expression of CD8+ T cells induced by HD-S1-presenting DCs were aberrantly lower than those induced by LD-S1-presenting DCs from day three of incubation. Discrepantly, the levels of lymphoproliferation and cytokine (interferon-γ and tumor necrosis factor-α) production induced by HD-S1-presenting DCs were significantly higher than those induced by LD-S1-presenting DCs from day four. The dose-related responses between doses of S1 and intracellular perforin expression showed a significant linear correlation with a negative slope. In conclusion, the S1 subunit may suppress the perforin expression in CD8+ T cells to decrease the cytotoxic capacity to kill spike-presenting cells in a dose-dependent manner; the persistence of antigen presentation may result in an overproduction of interferon-γ and subsequent proinflammatory cytokines. That may help explain the insufficient cytotoxicity against high quantities of viruses or highly replicated strains of SARS-CoV-2 in severe cases of COVID-19.

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CD4 T cells of prostate cancer patients have decreased immune responses to antigens derived from SARS-CoV-2 spike glycoprotein

10.21203/rs.3.rs-58545/v1 ◽

2020 ◽

Author(s):

Pavla Taborska ◽

Zuzana Strizova ◽

Dmitry Stakheev ◽

Ludek Sojka ◽

Jirina Bartunkova ◽

...

Keyword(s):

Prostate Cancer ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Cancer Patients ◽

Vaccine Development ◽

Adaptive Immune Response ◽

Cross Reactivity ◽

Spike Glycoprotein ◽

T Cell Immune Responses

Abstract The adaptive immune response to severe acute respiratory coronavirus 2 (SARS-CoV-2) is important for vaccine development and coronavirus disease 2019 (COVID-19) recovery. Men and cancer patients have been reported to be at higher risks of contracting the virus and developing severe COVID-19. Prostate cancer (PCa) may be associated with both of these risks. We show that CD4+ T cells of SARS-CoV-2-unexposed patients with hormone-refractory (HR) metastatic PCa have substantially decreased CD4+ T cell immune responses to antigens from SARS-CoV-2 spike glycoprotein but not from the spiked glycoprotein of the 'common cold'-associated human coronavirus 229E (HCoV-229E) as compared with healthy male volunteers. Moreover, the HCoV-229E spike glycoprotein antigen-elicited CD4+ T cell immune responses cross-reacted with the SARS-CoV-2 spiked glycoprotein antigens. PCa patients may not respond to the vaccination, and the cross-reactivity can mediate antibody-dependent enhancement (ADE) of COVID-19. These findings highlight the potential for increased vulnerability of PCa patients to COVID-19.

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SARS-CoV-2 spike glycoprotein-reactive T cells can be readily expanded from COVID-19 vaccinated donors

10.1101/2021.05.27.446089 ◽

2021 ◽

Author(s):

Pavla Taborska ◽

Jan Lastovicka ◽

Dmitry Stakheev ◽

Zuzana Strizova ◽

Jirina Bartunkova ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Cultures ◽

Cd8 T Cells ◽

Large Scale ◽

Ex Vivo ◽

Humoral Response ◽

Rapid Expansion ◽

Spike Glycoprotein ◽

Expansion Protocol

Introduction: The COVID-19 vaccine was designed to provide protection against infection by the severe respiratory coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19). However, the vaccine's efficacy can be compromised in patients with immunodeficiencies or the vaccine-induced immunoprotection suppressed by other comorbidity treatments, such as chemotherapy or immunotherapy. To enhance the protective role of the COVID-19 vaccine, we have investigated a combination of the COVID-19 vaccination with ex vivo enrichment and large-scale expansion of SARS-CoV-2 spike glycoprotein-reactive CD4+ and CD8+ T cells. Methods: SARS-CoV-2-unexposed donors were vaccinated with two doses of the BNT162b2 SARS-CoV-2 vaccine. The peripheral blood mononuclear cells of the vaccinated donors were cell culture-enriched with T cells reactive to peptides derived from SARS-CoV-2 spike glycoprotein. The enriched cell cultures were large-scale expanded using the rapid expansion protocol (REP) and the peptide-reactive T cells evaluated. Results: We show that vaccination with the SARS-CoV-2 spike glycoprotein-based mRNA COVID-19 vaccine induced humoral response against SARS-CoV-2 spike glycoprotein in all tested healthy SARS-CoV-2-unexposed donors. This humoral response was found to correlate with the ability of the donors' PBMCs to become enriched with SARS-CoV-2 spike glycoprotein-reactive CD4+ and CD8+ T cells. Using an 11-day rapid expansion protocol, the enriched cell cultures were expanded nearly a thousand fold, and the proportions of the SARS-CoV-2 spike glycoprotein-reactive T cells increased. Conclusions: These findings show for the first time that the combination of the COVID-19 vaccination and ex vivo T cell large-scale expansion of SARS-CoV-2-reactive T cells could be a powerful tool for developing T cell-based adoptive cellular immunotherapy of COVID-19.

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