IFN-γ derived from activated human CD4 ⁺ T cells inhibits the replication of SARS-CoV-2 depending on cell-type and viral strain.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

SARS-CoV-2*/immunology ; SARS-CoV-2*/physiology ; CD4-Positive T-Lymphocytes*/immunology ; CD4-Positive T-Lymphocytes*/virology ; Interferon-gamma*/metabolism ; Virus Replication* ; COVID-19*/virology ; COVID-19*/immunology; Humans ; Lymphocyte Activation/immunology ; Vero Cells ; Chlorocebus aethiops

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit both T cell and B cell immune responses in immunocompetent individuals. However, the mechanisms underlying the antiviral effects mediated by CD4 ⁺ T cells are not fully understood. In this study, we analyzed the culture supernatant (SN) from polyclonally stimulated human CD4 ⁺ T cells as a model for soluble mediators derived from SARS-CoV-2-stimulated CD4 ⁺ T cells. Interestingly, this SN inhibited SARS-CoV-2 propagation in a viral strain- and host cell type-dependent manner. The original wild-type showed the highest susceptibility, whereas the Delta variant exhibited resistance in the human monocyte cell line. In addition, antibody-dependent enhancement (ADE) of infection with the original strain was also abolished in the presence of the SN. The findings showed that the inhibitory effect on viral propagation by the SN was mostly attributed to interferon-γ (IFN-γ) that was present in the SN. These results highlight the potential role of IFN-γ as an anti-SARS-CoV-2 mediator derived from CD4 ⁺ T cells, and suggest that we need to understand the SARS-CoV-2 strain-dependent sensitivity to IFN-γ in controlling clinical outcomes. In addition, characterization of new SARS-CoV-2 variants in terms of IFN-γ-sensitivity will have important implications for selecting therapeutic strategies.
(© 2024. The Author(s).)

Moss, P. The T cell immune response against SARS-CoV-2. Nat. Immunol. 23, 186–193 (2022). (PMID: 10.1038/s41590-021-01122-w35105982)
Sette, A., Sidney, J. & Crotty, S. T cell responses to SARS-CoV-2. Annu. Rev. Immunol. 41, 343–373 (2023). (PMID: 10.1146/annurev-immunol-101721-06112036750314)
Wang, X. et al. Vaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response. Nat. Commun. 14, 3440 (2023). (PMID: 10.1038/s41467-023-39096-y3730191010257169)
Huot, N. et al. SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells. Nat. Immunol. 24, 2068–2079 (2023). (PMID: 10.1038/s41590-023-01661-43791952410681903)
Tarke, A. et al. SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from Alpha to Omicron. Cell 185, 847-859.e811 (2022). (PMID: 10.1016/j.cell.2022.01.015351393408784649)
Tarke, A. et al. Impact of SARS-CoV-2 variants on the total CD4(+) and CD8(+) T cell reactivity in infected or vaccinated individuals. Cell Rep. Med. 2, 100355 (2021). (PMID: 10.1016/j.xcrm.2021.100355342309178249675)
Loyal, L. et al. Cross-reactive CD4(+) T cells enhance SARS-CoV-2 immune responses upon infection and vaccination. Science 374, eabh1823 (2021). (PMID: 10.1126/science.abh18233446563310026850)
Braun, J. et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature 587, 270–274 (2020). (PMID: 10.1038/s41586-020-2598-932726801)
Grifoni, A. et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 181, 1489-1501.e1415 (2020). (PMID: 10.1016/j.cell.2020.05.015324731277237901)
Mateus, J. et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 370, 89–94 (2020). (PMID: 10.1126/science.abd3871327535547574914)
Le Bert, N. et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 584, 457–462 (2020). (PMID: 10.1038/s41586-020-2550-z32668444)
Shimizu, J. et al. Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells. Sci. Rep. 12, 15612 (2022). (PMID: 10.1038/s41598-022-19993-w361142249481526)
Shimizu, J. et al. The potential of COVID-19 patients’ sera to cause antibody-dependent enhancement of infection and IL-6 production. Sci. Rep. 11, 23713 (2021). (PMID: 10.1038/s41598-021-03273-0348875018660863)
Schneider, W. M., Chevillotte, M. D. & Rice, C. M. Interferon-stimulated genes: a complex web of host defenses. Annu. Rev. Immunol. 32, 513–545 (2014). (PMID: 10.1146/annurev-immunol-032713-120231245554724313732)
Busnadiego I, et al. Antiviral activity of type I, II, and III interferons counterbalances ACE2 inducibility and restricts SARS-CoV-2. mBio 11, (2020).
Schoggins, J. W. Interferon-stimulated genes: what do they all do?. Annu. Rev. Virol. 6, 567–584 (2019). (PMID: 10.1146/annurev-virology-092818-01575631283436)
Saleiro D, et al. IFN-γ-inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5. Sci. Signal 11, (2018).
Rydyznski Moderbacher C, et al. NVX-CoV2373 vaccination induces functional SARS-CoV-2-specific CD4 ⁺ and CD8 ⁺ T cell responses. J. Clin. Investig. 132, (2022).
Barreiro, P. et al. A pilot study for the evaluation of an interferon gamma release assay (IGRA) to measure T-cell immune responses after SARS-CoV-2 infection or vaccination in a unique cloistered cohort. J. Clin. Microbiol. 60, e0219921 (2022). (PMID: 10.1128/jcm.02199-2135020419)
Motozono, C. et al. The SARS-CoV-2 omicron BA.1 spike G446S mutation potentiates antiviral T-cell recognition. Nat. Commun. 13, 5440 (2022). (PMID: 10.1038/s41467-022-33068-4361309299492656)
Gil-Bescós R, et al. Potency assessment of IFNγ-producing SARS-CoV-2-specific T cells from COVID-19 convalescent subjects. Life Sci. Alliance. 6, (2023).
Krishna, B. A. et al. Spontaneous, persistent, T cell-dependent IFN-γ release in patients who progress to Long Covid. Sci. Adv. 10, eadi9379 (2024). (PMID: 10.1126/sciadv.adi93793838182210881041)
Lin, F. C. & Young, H. A. Interferons: Success in anti-viral immunotherapy. Cytokine Growth Factor Rev. 25, 369–376 (2014). (PMID: 10.1016/j.cytogfr.2014.07.015251564214182113)
Fensterl, V. & Sen, G. C. Interferons and viral infections. Biofactors 35, 14–20 (2009). (PMID: 10.1002/biof.619319841)
Park, A. & Iwasaki, A. Type I and Type III interferons—induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe 27, 870–878 (2020). (PMID: 10.1016/j.chom.2020.05.008324640977255347)
Gudima, G., Kofiadi, I., Shilovskiy, I., Kudlay, D., Khaitov, M. Antiviral therapy of COVID-19. Int. J. Mol. Sci. 24, (2023).
Lokugamage KG, et al. Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV. J. Virol. 94, (2020).
Vanderheiden A, et al. Type I and Type III interferons restrict SARS-CoV-2 infection of human airway epithelial cultures. J. Virol. 94, (2020).
Kang, S., Brown, H. M. & Hwang, S. Direct antiviral mechanisms of interferon-gamma. Immune Netw. 18, e33 (2018). (PMID: 10.4110/in.2018.18.e33304023286215902)
Akamatsu, M. A., de Castro, J. T., Takano, C. Y. & Ho, P. L. Off balance: Interferons in COVID-19 lung infections. EBioMedicine 73, 103642 (2021). (PMID: 10.1016/j.ebiom.2021.103642346786098524139)
Yang, D. et al. Type-II IFN inhibits SARS-CoV-2 replication in human lung epithelial cells and ex vivo human lung tissues through indoleamine 2,3-dioxygenase-mediated pathways. J. Med. Virol. 96, e29472 (2024). (PMID: 10.1002/jmv.2947238373201)
Silva, B. J. A. et al. IFN-γ-mediated control of SARS-CoV-2 infection through nitric oxide. Front. Immunol. 14, 1284148 (2023). (PMID: 10.3389/fimmu.2023.12841483816265310755032)
Karki, R. et al. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes. Cell 184, 149-168.e117 (2021). (PMID: 10.1016/j.cell.2020.11.02533278357)
Sadanandam, A. et al. A blood transcriptome-based analysis of disease progression, immune regulation, and symptoms in coronavirus-infected patients. Cell Death Discov. 6, 141 (2020). (PMID: 10.1038/s41420-020-00376-x332935147721861)
Haruta, M. et al. TAP-deficient human iPS cell-derived myeloid cell lines as unlimited cell source for dendritic cell-like antigen-presenting cells. Gene Ther. 20, 504–513 (2013). (PMID: 10.1038/gt.2012.5922875043)
Imamura, Y. et al. Generation of large numbers of antigen-expressing human dendritic cells using CD14-ML technology. PLoS One 11, e0152384 (2016). (PMID: 10.1371/journal.pone.0152384270505534822879)
Yamamoto, Y. et al. Long-term expansion of alveolar stem cells derived from human iPS cells in organoids. Nat. Methods 14, 1097–1106 (2017). (PMID: 10.1038/nmeth.444828967890)

JP20he0822004 the Japan Agency for Medical Research and Development (AMED)

82115-62-6 (Interferon-gamma)

SARS-CoV-2 variants

Date Created: 20241104 Date Completed: 20241104 Latest Revision: 20241107

20250114

PMC11535250

10.1038/s41598-024-77969-4

39496837