Exhaustion and Over-activation of Immune Cells in COVID-19: Challenges and Therapeutic Opportunities

Overview

Journal Clin Immunol

Specialty Allergy & Immunology

Date 2022 Nov 10

PMID 36356848

Authors

Murad Alahdal

Eyad Elkord

Affiliations

Soon will be listed here.

Abstract

Exhaustion of immune cells in COVID-19 remains a serious concern for infection management and therapeutic interventions. As reported, immune cells such as T effector cells (Teff), T regulatory cells (Tregs), natural killer cells (NKs), and antigen-presenting cells (APCs) exhibit uncontrolled functions in COVID-19. Unfortunately, the mechanisms that orchestrate immune cell functionality and virus interaction are still unknown. Recent studies linked adaptive immune cell exhaustion to underlying epigenetic mechanisms that regulate the epigenetic transcription of inhibitory immune checkpoint receptors (ICs). Further to that, the over-activation of T cells accompanied by the dysfunctionality of DCs and Tregs may enhance uncontrollable alveoli inflammation and cytokine storm in COVID-19. This might explain the reasons behind the failure of DC-based vaccines in inducing sufficient anti-viral responses. This review explains the processes behind the over-activation and exhaustion of innate and adaptive immune cells in COVID-19, which may contribute to developing novel immune intervention strategies.

Citing Articles

Harnessing Epigenetics: Innovative Approaches in Diagnosing and Combating Viral Acute Respiratory Infections.

Saha A, Ganguly A, Kumar A, Srivastava N, Pathak R Pathogens. 2025; 14(2).

PMID: 40005506 PMC: 11858160. DOI: 10.3390/pathogens14020129.

The causal effect of natural killer cells on COVID-19 infection, hospitalization and severity.

Yang K, Quan J, Liu Z, Huang Z, Wang S, Li J Inflamm Res. 2025; 74(1):37.

PMID: 39945857 DOI: 10.1007/s00011-024-01967-5.

Longitudinal Follow-Up of the Specific Antibody Response to SARS-CoV-2 Vaccination in Colombia.

Arevalo-Herrera M, Rincon-Orozco B, Gonzalez-Escobar J, Herrera-Arevalo S, Carrasquilla-Agudelo E, Serna-Ortega P J Med Virol. 2025; 97(1):e70133.

PMID: 39817585 PMC: 11737005. DOI: 10.1002/jmv.70133.

The COVID-19 Pandemic Heightens Interest in Cytokine Storm Disease and Advances in Machine Learning Diagnosis, Telemedicine, and Primordial Prevention of Rheumatic Diseases.

Koga T, Kawashiri S, Nonaka F, Tsuji Y, Tamai M, Kawakami A Eur J Rheumatol. 2024; 11(4):410-417.

PMID: 39651898 PMC: 11639611. DOI: 10.5152/eurjrheum.2024.23059.

Immunosuppressants in dermatology on vaccine immunogenicity: a prospective cohort study of pemphigus patients in the pandemic.

Lu K, Lee H, Chen C, Hui R, Chang Y, Lu C Front Immunol. 2024; 15:1506962.

PMID: 39650667 PMC: 11621035. DOI: 10.3389/fimmu.2024.1506962.

References

Yaqinuddin A, Kashir J . Innate immunity in COVID-19 patients mediated by NKG2A receptors, and potential treatment using Monalizumab, Cholroquine, and antiviral agents. Med Hypotheses. 2020; 140:109777. PMC: 7194824. DOI: 10.1016/j.mehy.2020.109777. View

Rivas J, Liu Y, Alhakeem S, Eckenrode J, Marti F, Collard J . Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia. Leukemia. 2021; 35(11):3188-3200. PMC: 8446094. DOI: 10.1038/s41375-021-01217-1. View

Braun J, Loyal L, Frentsch M, Wendisch D, Georg P, Kurth F . SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature. 2020; 587(7833):270-274. DOI: 10.1038/s41586-020-2598-9. View

Tavakolpour S, Rakhshandehroo T, Wei E, Rashidian M . Lymphopenia during the COVID-19 infection: What it shows and what can be learned. Immunol Lett. 2020; 225:31-32. PMC: 7305732. DOI: 10.1016/j.imlet.2020.06.013. View

Alahdal M, Xing Y, Tang T, Liang J . 1-Methyl-D-tryptophan Reduces Tumor CD133 cells, Wnt/β-catenin and NF-κβp65 while Enhances Lymphocytes NF-κβ2, STAT3, and STAT4 Pathways in Murine Pancreatic Adenocarcinoma. Sci Rep. 2018; 8(1):9869. PMC: 6026162. DOI: 10.1038/s41598-018-28238-8. View

Channappanavar R, Zhao J, Perlman S . T cell-mediated immune response to respiratory coronaviruses. Immunol Res. 2014; 59(1-3):118-28. PMC: 4125530. DOI: 10.1007/s12026-014-8534-z. View

Ma-Lauer Y, Carbajo-Lozoya J, Hein M, Muller M, Deng W, Lei J . p53 down-regulates SARS coronavirus replication and is targeted by the SARS-unique domain and PLpro via E3 ubiquitin ligase RCHY1. Proc Natl Acad Sci U S A. 2016; 113(35):E5192-201. PMC: 5024628. DOI: 10.1073/pnas.1603435113. View

Nelemans T, Kikkert M . Viral Innate Immune Evasion and the Pathogenesis of Emerging RNA Virus Infections. Viruses. 2019; 11(10). PMC: 6832425. DOI: 10.3390/v11100961. View

Baccala R, Gonzalez-Quintial R, Lawson B, Stern M, Kono D, Beutler B . Sensors of the innate immune system: their mode of action. Nat Rev Rheumatol. 2009; 5(8):448-56. DOI: 10.1038/nrrheum.2009.136. View

10.

Fehr A, Channappanavar R, Perlman S . Middle East Respiratory Syndrome: Emergence of a Pathogenic Human Coronavirus. Annu Rev Med. 2016; 68:387-399. PMC: 5353356. DOI: 10.1146/annurev-med-051215-031152. View

11.

Jan de Heer H, Hammad H, Soullie T, Hijdra D, Vos N, Willart M . Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med. 2004; 200(1):89-98. PMC: 2213319. DOI: 10.1084/jem.20040035. View

12.

Antonioli L, Fornai M, Pellegrini C, Blandizzi C . NKG2A and COVID-19: another brick in the wall. Cell Mol Immunol. 2020; 17(6):672-674. PMC: 7203720. DOI: 10.1038/s41423-020-0450-7. View

13.

Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A, Wang Y . TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8 T cell exhaustion. Proc Natl Acad Sci U S A. 2019; 116(25):12410-12415. PMC: 6589758. DOI: 10.1073/pnas.1905675116. View

14.

Frieder J, Kivelevitch D, Menter A . Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chronic Dis. 2018; 9(1):5-21. PMC: 5761942. DOI: 10.1177/2040622317738910. View

15.

Cui X, Chen W, Zhou H, Gong Y, Zhu B, Lv X . Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential. Front Pharmacol. 2021; 12:664349. PMC: 8215379. DOI: 10.3389/fphar.2021.664349. View

16.

Shin H, Blackburn S, Intlekofer A, Kao C, Angelosanto J, Reiner S . A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity. 2009; 31(2):309-20. PMC: 2747257. DOI: 10.1016/j.immuni.2009.06.019. View

17.

Kalfaoglu B, Almeida-Santos J, Tye C, Satou Y, Ono M . T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis. Front Immunol. 2020; 11:589380. PMC: 7596772. DOI: 10.3389/fimmu.2020.589380. View

18.

Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C . Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8(4):420-422. PMC: 7164771. DOI: 10.1016/S2213-2600(20)30076-X. View

19.

Kim T, Lee H . Differential roles of lung dendritic cell subsets against respiratory virus infection. Immune Netw. 2014; 14(3):128-37. PMC: 4079819. DOI: 10.4110/in.2014.14.3.128. View

20.

Judge S, Murphy W, Canter R . Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence. Front Cell Infect Microbiol. 2020; 10:49. PMC: 7031155. DOI: 10.3389/fcimb.2020.00049. View