Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)
Journal: 2020/May - Frontiers in Immunology
Abstract:
Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear. Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. In addition, the expression of T cell exhaustion markers were measured in 14 COVID-19 cases. Results: The number of total T cells, CD4+ and CD8+ T cells were dramatically reduced in COVID-19 patients, especially in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8+ T cells or CD4+ T cells lower than 800, 300, or 400/μL, respectively, were negatively correlated with patient survival. T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration, with patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients had significantly higher levels of the exhausted marker PD-1. Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages. Conclusions: T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients with total T cells counts lower than 800/μL may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.
Keywords: COVID-19; SARS- CoV-2; T cell exhaustion; T cell reduction; cytokine strom.
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Front Immunol 11: 827

Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)

+6 authors
Department of Medical Laboratory Center, General Hospital of Central Theater Command, Wuhan, China
Institute of Immunology, PLA, Third Military Medical University, Chongqing, China
Medical English Department, College of Basic Medical Sciences, Army Medical University, Chongqing, China
Department of Medical Laboratory Medicine, General Hospital of Central Theater Command, Wuhan, China
Hanyang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
Edited by: Stefano Caserta, University of Hull, United Kingdom
Reviewed by: Nadia Maria Terrazzini, University of Brighton, United Kingdom; Jessica Borger, Monash University, Australia
*Correspondence: Yuzhang Wu nc.ude.ummt@gnahzuyuw
Yongwen Chen moc.361@hcnewgnoy
This article was submitted to Immunological Memory, a section of the journal Frontiers in Immunology
†These authors have contributed equally to this work
Edited by: Stefano Caserta, University of Hull, United Kingdom
Reviewed by: Nadia Maria Terrazzini, University of Brighton, United Kingdom; Jessica Borger, Monash University, Australia
Received 2020 Mar 21; Accepted 2020 Apr 14.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear.

Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. In addition, the expression of T cell exhaustion markers were measured in 14 COVID-19 cases.

Results: The number of total T cells, CD4 and CD8 T cells were dramatically reduced in COVID-19 patients, especially in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8 T cells or CD4 T cells lower than 800, 300, or 400/μL, respectively, were negatively correlated with patient survival. T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration, with patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients had significantly higher levels of the exhausted marker PD-1. Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages.

Conclusions: T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients with total T cells counts lower than 800/μL may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.

Keywords: SARS- CoV-2, COVID-19, T cell reduction, T cell exhaustion, cytokine strom

Acknowledgments

This manuscript has been released as a preprint at MedRxiv (39).

Footnotes

Funding. This work was supported by the National Key Research and Development Program of China (No. 2016YFA0502204) and the National Natural Science Foundation of China (NSFC; Nos. 91442203, 81361120400, 91442203, 81471862, and 8177169).

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References

  • 1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. . A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. (2020) 382:727–33. 10.1056/NEJMoa2001017 ] [
  • 2. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. . Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. (2020) 382:1199–207. 10.1056/NEJMoa2001316 ] [
  • 3. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. . Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. (2020) 395:565–74. 10.1016/S0140-6736(20)30251-8 ] [
  • 4. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. (2020) 395:497–506. 10.1016/S0140-6736(20)30183-5 ] [
  • 5. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. . Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. (2020) 395:507–13. 10.1016/S0140-6736(20)30211-7 ] [
  • 6. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. . Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. (2020) e201585. 10.1001/jama.2020.1585. [Epub ahead of print]. ] [
  • 7. National Health Commission of the People's Republic of China The Latest Situation of Novel Coronavirus Pneumonia as of 24:00 on 20 March 2020. Available online at: (accessed March 21, 2020).[PubMed]
  • 8. Li CK, Wu H, Yan H, Ma S, Wang L, Zhang M, et al. . T cell responses to whole SARS coronavirus in humans. J Immunol. (2008) 181:5490–500. 10.4049/jimmunol.181.8.5490 ] [
  • 9. National Health Commission of the People's Republic of China The Notice of Launching Guideline on Diagnosis and Treatment of the Novel Coronavirus Pneumonia (NCP). 5th ed Available online at: (accessed February 18, 2020).[PubMed]
  • 10. Nina P, Mark S, Anh-Hue TT, Brian MF, Ohilip L. Characteristics of Infectious Disease. Microbiology (2016). Available online at: [PubMed]
  • 11. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. (2020) 579:270–3. 10.1038/s41586-020-2012-7 ] [
  • 12. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. (2015) 15:486–99. 10.1038/nri3862 ] [
  • 13. Mescher MF, Curtsinger JM, Agarwal P, Casey KA, Gerner M, Hammerbeck CD, et al. . Signals required for programming effector and memory development by CD8+ T cells. Immunol Rev. (2006) 211:81–92. 10.1111/j.0105-2896.2006.00382.x [] [[PubMed]
  • 14. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (). Annu Rev Immunol. (2010) 28:445–89. 10.1146/annurev-immunol-030409-101212 ] [
  • 15. Ng CT, Snell LM, Brooks DG, Oldstone MB. Networking at the level of host immunity: immune cell interactions during persistent viral infections. Cell Host Microbe. (2013) 13:652–64. 10.1016/j.chom.2013.05.014 ] [
  • 16. Fenwick C, Joo V, Jacquier P, Noto A, Banga R, Perreau M, et al. . T-cell exhaustion in HIV infection. Immunol Rev. (2019) 292:149–63. 10.1111/imr.12823 ] [
  • 17. Wang H, Ma S. The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome. Am J Emerg Med. (2008) 26:711–5. 10.1016/j.ajem.2007.10.031 [] [[PubMed]
  • 18. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. (2012) 122:2731–40. 10.1172/JCI60331 ] [
  • 19. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. (2017) 39:529–39. 10.1007/s00281-017-0629-x ] [
  • 20. Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, et al. . An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. (2005) 75:185–94. 10.1002/jmv.20255 ] [
  • 21. Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med. (2008) 358:261–73. 10.1056/NEJMra0707279 [] [[PubMed]
  • 22. Chen Y, Liang W, Yang S, Wu N, Gao H, Sheng J, et al. . Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet. (2013) 381:1916–25. 10.1016/S0140-6736(13)60903-4 ] [
  • 23. Aggarwal S, Gollapudi S, Gupta S. Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: changes in TNF-alpha receptor expression and activation of caspases. J Immunol. (1999) 162:2154–61. [[PubMed]
  • 24. Gupta S, Bi R, Kim C, Chiplunkar S, Yel L, Gollapudi S. Role of NF-kappaB signaling pathway in increased tumor necrosis factor-alpha-induced apoptosis of lymphocytes in aged humans. Cell Death Differ. (2005) 12:177–83. 10.1038/sj.cdd.4401557 [] [[PubMed]
  • 25. Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther. (2006) 8:S3. 10.1186/ar1917 ] [
  • 26. Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. (2018) 18:773–89. 10.1038/s41577-018-0066-7 [] [[PubMed]
  • 27. Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Kelman A, et al. . Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. (2016) 75:1081–91. 10.1136/annrheumdis-2015-207628 ] [
  • 28. Yokota S, Itoh Y, Morio T, Origasa H, Sumitomo N, Tomobe M, et al. . Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan. Ann Rheum Dis. (2016) 75:1654–60. 10.1136/annrheumdis-2015-207818 ] [
  • 29. Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. . FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. (2018) 23:943. 10.1634/theoncologist.2018-0028 ] [
  • 30. Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci. (2019) 20:6008. 10.3390/ijms20236008 ] [
  • 31. Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, et al. . Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Arch Immunol Ther Exp. (2016) 64:111–26. 10.1007/s00005-015-0377-3 [] [[PubMed]
  • 32. Yang C, Chen Y, Guo G, Li H, Cao D, Xu H, et al. . Expression of B and T lymphocyte attenuator (BTLA) in macrophages contributes to the fulminant hepatitis caused by murine hepatitis virus strain-3. Gut. (2013) 62:1204–13. 10.1136/gutjnl-2012-302239 [] [[PubMed]
  • 33. Li J, Diao B, Guo S, Huang X, Yang C, Feng Z, et al. . VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism. Nat Commun. (2017) 8:1322. 10.1038/s41467-017-01327-4 ] [
  • 34. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Ann Rev Immunol. (2019) 37:457–95. 10.1146/annurev-immunol-041015-055318 [] [[PubMed]
  • 35. Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med. (2006) 12:1301–9. 10.1038/nm1492 ] [
  • 36. Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, Crotty S, et al. . Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med. (2006) 203:2461–72. 10.1084/jem.20061462 ] [
  • 37. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. . Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. (2020) 30:269–71. 10.1038/s41422-020-0282-0 ] [
  • 38. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. . First Case of 2019 novel coronavirus in the United States. N Engl J Med. (2020) 382:929–36. 10.1056/NEJMoa2001191 ] [
  • 39. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). medRxiv. (2020) 2020.02.18.20024364. 10.1101/2020.02.18.20024364 [[PubMed][Google Scholar]
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