Divergent SARS-CoV-2-specific T- and B-cell responses in severe but not mild COVID-19 patients

Anna E Oja, Anno Saris, Cherien A Ghandour, Natasja A M Kragten, Boris M Hogema, Esther J Nossent, Leo M A Heunks, Susan Cuvalay, Ed Slot, Federica Linty, Francis H Swaneveld, Hans Vrielink, Gestur Vidarsson, Theo Rispens, Ellen van der Schoot, René A W van Lier, Anja Ten Brinke, Pleun Hombrink, Anna E Oja, Anno Saris, Cherien A Ghandour, Natasja A M Kragten, Boris M Hogema, Esther J Nossent, Leo M A Heunks, Susan Cuvalay, Ed Slot, Federica Linty, Francis H Swaneveld, Hans Vrielink, Gestur Vidarsson, Theo Rispens, Ellen van der Schoot, René A W van Lier, Anja Ten Brinke, Pleun Hombrink

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. Understanding the immune response that provides specific immunity but may also lead to immunopathology is crucial for the design of potential preventive and therapeutic strategies. Here, we characterized and quantified SARS-CoV-2-specific immune responses in patients with different clinical courses. Compared to individuals with a mild clinical presentation, CD4+ T-cell responses were qualitatively impaired in critically ill patients. Strikingly, however, in these patients the specific IgG antibody response was remarkably strong. Furthermore, in these critically ill patients, a massive influx of circulating T cells into the lungs was observed, overwhelming the local T-cell compartment, and indicative of vascular leakage. The observed disparate T- and B-cell responses could be indicative of a deregulated immune response in critically ill COVID-19 patients.

Keywords: CD4+ T cells; COVID-19; IgG; SARS-CoV-2; antibody response.

© 2020 Wiley-VCH GmbH.

References

    1. Dong, E., Du, H. and Gardner, L., COVID-19 in real time. Lancet Infect. Dis. 2020. 20: 533-534.
    1. Guan, W., Ni, Z., Hu, Y., Liang, W., Ou, C., He, J., Liu, L. et al., Clinical characterisitics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020. 382: 1708-1720.https://.
    1. Tay, M. Z., Poh, C. M., Rénia, L., Macary, P. A. and Ng, L. F. P., The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 2020. 20: 363-374.
    1. Yang, X., Yu, Y., Xu, J., Shu, H., Xia, J., Liu, H., Wu, Y. et al., Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. 2020. 8:475-481.
    1. Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., Liu, S. et al., Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. 2020. 8: 420-422.
    1. Zhao, J., Zhao, J., Mangalam, A. K., Channappanavar, R., Fett, C., Meyerholz, D. K., Agnihothram, S. et al., Airway memory CD4+ T cells mediate protective immunity against emerging respiratory coronaviruses. Immunity 2016. 44: 1379-1391.
    1. Liao, M., Liu, Y., Yuan, J., Wen, Y., Xu, G., Zhao, J., Cheng, L. et al., Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat. Med. 2020. 26: 842-844.
    1. Braun, J., Loyal, L., Frentsch, M., Wendisch, D., Georg, P., Kurth, F., Hippenstiel, S. et al., SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature 2020. .
    1. Grifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., Rawlings, S. A. et al., Targets of T-cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 2020. 1-13.
    1. Thevarajan, I., Nguyen, T. H. O., Koutsakos, M., Druce, J., Caly, L., van de Sandt, C. E., Jia, X. et al., Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat. Med. 2020. 1: 1-3.
    1. Weiskopf, D., Schmitz, K. S., Raadsen, M. P., Grifoni, A., Okba, N. M. A., Endeman, H., Molenkamp, R. et al., Phenotype of SARS-CoV-2-specific T-cells in COVID-19 patients with acute respiratory distress syndrome. medRxiv 2020. 1-20.
    1. Mateus, J., Grifoni, A., Tarke, A., Sidney, J., Ramirez, S. I., Dan, J. M., Burger, Z. C. et al., Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science. 2020. 370:89-94.
    1. Feng, Z., Diao, B., Wang, R., Wang, G., Wang, C., Tan, Y., Wang, C. et al., The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes running title : SARS-CoV-2 infects human spleens and lymph nodes. medRxiv 2020. 2: 1-18.
    1. Zheng, H., Zhang, M., Yang, C., Zhang, N., Wang, X., Yang, X., Dong, X. et al., Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cell. Mol. Immunol. 2020. 17-19.
    1. Wang, W., Su, B., Pang, L., Qiao, L., Feng, Y., Ouyang, Y., Guo, X. et al., High-dimensional immune profiling by mass cytometry revealed immunosuppression and dysfunction of immunity in COVID-19 patients. Cell. Mol. Immunol. 2020. 28-30. .
    1. Yang, X., Dai, T., Zhou, X., Qian, H., Guo, R., Lei, L., Zhang, X. et al., Analysis of adaptive immune cell populations and phenotypes in the patients infected by SARS-CoV-2. medRxiv 2020.
    1. Mathew, D., Deep immune profiling of COVID-19 patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions. bioRxiv 2020.
    1. Mudgal, G., Ordon, D., Enjuanes, L. and Reguera, J., Structural bases of coronavirus attachment to host aminopeptidase N and its inhibition by neutralizing antibodies.PLoS Pathog. 2012. 8: e1002859.
    1. Wang, C., Li, W., Drabek, D., Okba, N. M. A., Haperen, R. Van., Osterhaus, A. D. M. E., Kuppeveld, F. J. M. Van., et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat. Commun. 2020. 11: 1-6.
    1. Ni, L., Ye, F., Cheng, M., Qin, C., Chen, F., Ni, L., Ye, F. et al., Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals report detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity 2020. 1-7.https://.
    1. Mueller, S. N. and Mackay, L. K., Tissue-resident memory T cells: local specialists in immune defence. Nat. Publ. Gr. 2015. 16. .
    1. Szabo, P. A., Miron, M. and Farber, D. L., Location, location, location: tissue resident memory T cells in mice and humans. Sci. Immunol. 2019. 4: 1-12.
    1. Hombrink, P., Helbig, C., Backer, R. A., Piet, B., Oja, A. E., Stark, R., Brasser, G. et al., Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells. Nat. Immunol. 2016. 17: 1467-1478.
    1. Oja, A. E., Piet, B., Helbig, C., Stark, R., van der Zwan, D., Blaauwgeers, H., Remmerswaal, E. B. M. et al., Trigger-happy resident memory CD4+ T cells inhabit the human lungs. Mucosal Immunol. 2017. .
    1. Channappanavar, R., Fett, C., Zhao, J. and Meyerholz, D. K., Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection. J. Virol. 2014. 88: 11034-11044.
    1. Snyder, M. E., Finlayson, M. O., Connors, T. J., Dogra, P., Senda, T., Bush, E., Carpenter, D. et al., Generation and persistence of human tissue-resident memory T cells in lung transplantation. Sci. Immunol. 2019. 4: 1-17.
    1. Bos, R. and Sherman, L. A., CD4 + T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8 + T lymphocytes. Cancer Res. 2010. 70: 8368-8378.
    1. Schenkel, J. M., Fraser, K. A., Vezys, V. and Masopust, D., Sensing and alarm function of resident memory CD8(+) T cells. Nat Immunol. 2013. 14: 509-513.
    1. Sainz, B. and Halford, W. P.Alpha/beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type 1. J. Virol. 2002. 76: 11541-11550.
    1. Schroder, K., Hertzog, P. J., Ravasi, T., andHume, D. A., Interferon- gamma: an overview of signals, mechanisms and functions. J. Leukoc Biol. 2004. 75: 163-189.
    1. Lang, A. De., Osterhaus, A. D. M. E. and Haagmans, B. L., Interferon-γ and interleukin-4 downregulate expression of the SARS coronavirus receptor ACE2 in Vero E6 cells. Virology 2006. 353: 474-481.
    1. Cinatl, J., Morgenstern, B., Bauer, G., Chandra, P., Rabenau, H. and Doerr, H. W., Treatment of SARS with human interferons. Lancet 2003. 362: 293-294.
    1. Choreschi, K., Thomas, P., Breit, S., Dugas, M., Mailhammer, R., van Eden, W., van der Zee, R. et al., Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat. Med. 2003. 9: 40-46.
    1. Guenova, E., Skabytska, Y., Hoetzenecker, W., Weindl, G. and Sauer, K., IL-4 abrogates T H 17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells. Proc. Natl. Acad. Sci. US.A. 2015. 112: 2163-2168.
    1. Kamphorst, A. O., Wieland, A., Nasti, T., Yang, S., Zhang, R., Barber, D. L., Konieczny, B. T. et al., Rescue of exhausted CD8 T cells by PD-1: targeted therapies is CD28-dependent. Science 2017. 355: 1423-1427.
    1. Bektas, A., Schurman, S. H., Sen, R. and Ferrucci, L., Human T cell immunosenescence and inflammation in aging. J. Leukoc Biol. 2017. 102: 977-988.
    1. Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. and Santoro, A., Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 2018. 14: 576-590.
    1. Meftahi, G. H., Jangravi, Z., Sahraei, H. and Bahari, Z., The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection : the contribution of “ inflame-aging”. Inflamm. Res. 2020. 69: 825-839.
    1. Linterman, M. A., Beaton, L., Yu, D., Ramiscal, R. R., Srivastava, M., Hogan, J. J., Verma, N. K. et al., IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 2010. 207: 353-363.
    1. Grifoni, A., Sidney, J., Zhang, Y., Scheuermann, R. H., Peters, B., Sette, A., Grifoni, A. et al., Sequence homology and bioinformatic approach can predict candidate targets for immune responses to SARS-CoV-2 theory a sequence homology and bioinformatic approach can predict candidate targets for immune responses to SARS-CoV-2. Cell Host Microbe. 2020. 27: 671-680.e2.
    1. Ludvigsson, J. F., Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020. 109: 1088-1095.
    1. Peiris, J. S. M., Chu, C. M., Cheng, V. C. C., Chan, K. S., Hung, I. F. N., Poon, L. L. M., Law, K. I.,et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 2003. 361: 1767-1772.
    1. Oh, M., Park, W. B., Choi, S.-J., Kim, J.-I., Chae, J., Park, S. S., Kim, E.-C. et al., Viral load kinetics of MERS coronavirus infection. N. Engl. J. Med. 2016. 12-14.https://.
    1. Zou, L., Ruan, F., Huang, M., Liang, L., Huang, H., Hong, Z., Yu, J. et al.,SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N. Engl. J. Med. 2020. 1: 12-14.
    1. To, K. K., Tak, O., Tsang, Y., Leung, W., Tam, A. R., Wu, T., Lung, D. C. et al., Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect. Dis. 2020. 20: 565-574.
    1. Wölfel, R., Corman, V. M., Guggemos, W., Seilmaier, M., Zange, S., Müller, M. A., Niemeyer, D. et al., Virological assessment of hospitalized patients with COVID-2019. Nature. 2020. 581:465-469.
    1. Liu, L., Yuen, K., Chen, Z., Liu, L., Wei, Q., Lin, Q., Fang, J. et al., Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection Find the latest version: anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019. 4: e123158.
    1. Shaw, A. C., Goldstein, D. R. and Montgomery, R. R., Age-dependent dysregulation of innate immunity. Nat. Publ. Gr. 2013.13: 875-887.
    1. Wu, Y. and Chen, Y., Reduction and Functional Exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front. Immunol. 2020. 11: 1-7.
    1. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L. et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. 395: 497-506.
    1. Crotty, S., A brief history of T cell help to B cells. Nat. Rev. Immunol. 2015. 15: 185-189.
    1. He, J., Tsai, L. M., Leong, Y. A., Hu, X., Ma, C. S., Chevalier, N., Sun, X. et al., Circulating precursor CCR7loPD-1hi CXCR5+ CD4+ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 2013. 39: 770-781.
    1. Locci, M., Havenar-Daughton, C., Landais, E., Wu, J., Kroenke, M. A., Arlehamn, C. L., Su, L. F. et al., Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity 2013. 39: 758-769.
    1. Bentebibel, S., Lopez, S., Obermoser, G., Schmitt, N., Mueller, C., Harrod, C., Flano, E. et al., Induction of ICOS + CXCR3 + CXCR5 + T H cells correlates with antibody responses to influenza vaccination. bioRxiv 2013. 5: 1-11.
    1. Bentebibel, S., Khurana, S., Schmitt, N. and Kurup, P., ICOS+PD-1+CXCR3+ T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination. Nat. Publ. Gr. 2016. 1-8. .
    1. Spaan, M., Kreefft, K., Graav, G. N. De., Brouwer, W. P., Knegt, R. J. De., Kate, F. J. W., Baan, C. C. et al., CD4 + CXCR5 + T cells in chronic HCV infection produce less IL-21, yet are efficient at supporting B cell responses. J. Hepatol. 2015. 62: 303-310.
    1. Delbo Larsen, M., Graaf, E. L. De., Sonneveld, M. E., Plomp, H. R., Linty, F., Visser, R., Brinkhaus, M. et al., Afucosylated immunoglobulin G responses are a hallmark of enveloped virus infections and show an exacerbated phenotype in COVID-19. bioRxiv 2020.
    1. Li, L., Chow, V. T. K. and Tan, N. S., Targeting vascular leakage in lung inflammation. Oncotarget 2009. 6: 4-5.
    1. Channappanavar, R. and Perlman, S., Pathogenic human coronavirus infections : causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017. 39: 529-539.
    1. Piet, B., De Bree, G. J., Smids-Dierdorp, B. S., Van Der Loos, C. M., Remmerswaal, E. B. M., Von Der Thüsen, J. H., Van Haarst, J. M. W. et al., CD8+ T cells with an intraepithelial phenotype upregulate cytotoxic function upon influenza infection in human lung. J. Clin. Invest. 2011. 121: 2254-2263.
    1. Cossarizza, A., Chang, H. D., Radbruch, A., Acs, A., Adam, A., Adam-Klages, S., Agace, W. et al., Guidelines for the use of flow cytometry and cell sorting in immunological studies. Eur. J. Immunol. 2019. 49: 1457-1973.

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