Skip to main content

Advertisement

SpringerLink
Log in

The kinetics of inhibitory immune checkpoints during and post-COVID-19: the knowns and unknowns

  • Review
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

The immune system is tightly regulated to prevent immune reactions to self-antigens and to avoid excessive immune responses during and after challenges from non-self-antigens. Inhibitory immune checkpoints (IICPs), as the major regulators of immune system responses, are extremely important for maintaining the homeostasis of cells and tissues. However, the high and sustained co-expression of IICPs in chronic infections, under persistent antigenic stimulations, results in reduced immune cell functioning and more severe and prolonged disease complications. Furthermore, IICPs-mediated interactions can be hijacked by pathogens in order to evade immune induction or effector mechanisms. Therefore, IICPs can be potential targets for the prognosis and treatment of chronic infectious diseases. This is especially the case with regards to the most challenging infectious disease of recent times, coronavirus disease-2019 (COVID-19), whose long-term complications can persist long after recovery. This article reviews the current knowledge about the kinetics and functioning of the IICPs during and post-COVID-19.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and material

Not applicable.

Abbreviations

APC:

Antigen presenting cell

BMP4:

Bone morphogenetic protein 4

BTLA:

B and T lymphocyte attenuator

Ceacam-1:

Carcinoembryonic antigen associated cell adhesion molecules-1

CMV:

Cytomegalovirus

COVID-19:

Coronavirus disease 2019

CTLA-4:

Cytotoxic T lymphocyte antigen-4

CXCL10:

C–x–c motif chemokine ligand 10

DC:

Dendritic cell

DNAM-1:

DNAX accessory molecule-1

EAT2:

EWS-Fli1-activated transcript 2

EBV:

Epstein–Barr virus

EC:

Endothelial cell

FGL1:

Fibrinogen like 1

Gal-9:

Galectin-9

gD:

Glycoprotein D

GPI:

Glycosylphosphatidylinositol

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HIV:

Human immunodeficiency virus

HLA-I:

Human leukocyte antigen class-I

HMGB1:

High mobility group box-1

HSV:

Herpes simplex virus

HTLV-1:

Human T-lymphotropic virus type 1

HVEM:

Herpes virus entry mediator

ICP:

Immune checkpoint

ICU:

Intensive care unit

IEL:

Intraepithelial lymphocytes

IFN-γ:

Interferon-gamma

IgE/G:

Immunoglobulin E/G

IICP:

Inhibitory immune checkpoint

IL-4/10/12/13:

Interleukin 4/10/12/13

ILC3:

Innate lymphoid cell type 3

iNOS:

Inducible nitric oxide synthase

ITAM:

Immunoreceptor tyrosine-based activation motif

ITIM:

Immunoreceptor tyrosine-based inhibition motif

ITSM:

Immunoreceptor tyrosine-based switch motif

LAG-3:

Lymphocyte activation gene-3

LAIR-1:

Leukocyte-associated immunoglobulin-like receptor-1

LCMV:

Lymphocytic choriomeningitis virus

LSECtin:

Liver and lymph node sinusoidal endothelial cell C-type lectin

MDSC:

Myeloid-derived suppressor cell

MFI:

Mean fluorescent intensity

NK cell:

Natural killer cell

NKG2A:

NK group 2 member A

NKT:

Natural killer T

PBMC:

Peripheral blood mononuclear cell

PD-1:

Programmed cell death protein-1

pDC:

Plasmacytoid dendritic cell

PD-L1/2:

Programmed death-ligand ½

pMHCII:

Peptide-major histocompatibility complex-II

PRNT:

Plaque reduction neutralization test

PtdSer:

Phosphatidylserine

SAP:

SLAM-associated protein

SARS-CoV-2:

Severe acute respiratory syndrome-coronavirus-2

sCTLA-4:

Soluble CTLA-4

SHIP1:

Src homology region 2 domain-containing inositol phosphatase 1

sHLA-G:

Soluble HLA-G

SHP-1/2:

Src homology region 2 domain-containing phosphatase-1/2

SICP:

Stimulatory immune checkpoint

sLAG-3:

Soluble LAG-3

SLAMF4:

Signaling lymphocytic activating molecule family 4

SP1:

Spike protein 1

sTIM-3:

Soluble TIM-3

TCR:

T cell receptor

TIGIT:

T cell immunoglobulin and ITIM domain

TIM-3:

T-cell immunoglobulin and mucin domain-containing protein 3

TLR:

Toll-like receptor

TNFRSF14:

Tumor necrosis factor receptor superfamily member 14

TNF-α:

Tumor necrosis factor α

Tregs:

Regulatory T cell

VACV:

Vaccinia virus

VISTA:

V-type immunoglobulin domain-containing suppressor of T-cell activation

References

  1. Buckner JH, Ziegler SF. Regulating the immune system: the induction of regulatory T cells in the periphery. Arthritis Res Ther. 2004;6:215–22. https://doi.org/10.1186/ar1226.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Viganò S, Perreau M, Pantaleo G, Harari A. Positive and negative regulation of cellular immune responses in physiologic conditions and diseases. Clin Dev Immunol Res. 2012;2012:485781. https://doi.org/10.1155/2012/485781.

    Article  CAS  Google Scholar 

  3. Li W, Syed F, Yu R, et al. Soluble immune checkpoints are dysregulated in COVID-19 and heavy alcohol users with HIV infection. Front Immunol. 2022;13:833310. https://doi.org/10.3389/fimmu.2022.833310.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Walters AA, Dhadwar B, Al-Jamal KT. Modulating expression of inhibitory and stimulatory immune ‘checkpoints’ using nanoparticulate-assisted nucleic acid delivery. EBioMedicine. 2021;73:103624. https://doi.org/10.1016/j.ebiom.2021.103624.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Marin-Acevedo JA, Dholaria B, Soyano AE, Knutson KL, Chumsri S, Lou Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol. 2018;11:39. https://doi.org/10.1186/s13045-018-0582-8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Wykes MN, Lewin SR. Immune checkpoint blockade in infectious diseases. Nat Rev Immunol. 2018;18:91–104. https://doi.org/10.1038/nri.2017.112.

    Article  CAS  PubMed  Google Scholar 

  7. Tian X, Zhang A, Qiu C, et al. The upregulation of LAG-3 on T cells defines a subpopulation with functional exhaustion and correlates with disease progression in HIV-infected subjects. J Immunol. 2015;194:3873–82. https://doi.org/10.4049/jimmunol.1402176.

    Article  CAS  PubMed  Google Scholar 

  8. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44:989–1004. https://doi.org/10.1016/j.immuni.2016.05.001.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Okoye IS, Houghton M, Tyrrell L, Barakat K, Elahi S. Coinhibitory receptor expression and immune checkpoint blockade: maintaining a balance in CD8(+) T cell responses to chronic viral infections and cancer. Front Immunol. 2017;8:1215. https://doi.org/10.3389/fimmu.2017.01215.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9. https://doi.org/10.1038/ni.2035.

    Article  CAS  PubMed  Google Scholar 

  11. Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006;12:1198–202. https://doi.org/10.1038/nm1482.

    Article  CAS  PubMed  Google Scholar 

  12. Wu W, Shi Y, Li J, Chen F, Chen Z, Zheng M. Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection. Virol J. 2011;8:113. https://doi.org/10.1186/1743-422x-8-113.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Ackermann C, Smits M, Woost R, et al. HCV-specific CD4+ T cells of patients with acute and chronic HCV infection display high expression of TIGIT and other co-inhibitory molecules. Sci Rep. 2019;9:10624. https://doi.org/10.1038/s41598-019-47024-8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19:141–54. https://doi.org/10.1038/s41579-020-00459-7.

    Article  CAS  PubMed  Google Scholar 

  15. Fouladseresht H, Ghamar Talepoor A, Eskandari N, et al. Potential immune indicators for predicting the prognosis of COVID-19 and trauma: similarities and disparities. Front Immunol. 2021;12:785946. https://doi.org/10.3389/fimmu.2021.785946.

    Article  CAS  PubMed  Google Scholar 

  16. Leung NHL. Transmissibility and transmission of respiratory viruses. Nat Rev Microbiol. 2021;19:528–45. https://doi.org/10.1038/s41579-021-00535-6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Fouladseresht H, Doroudchi M, Rokhtabnak N, et al. Predictive monitoring and therapeutic immune biomarkers in the management of clinical complications of COVID-19. Cytokine Growth Factor Rev. 2021;58:32–48. https://doi.org/10.1016/j.cytogfr.2020.10.002.

    Article  CAS  PubMed  Google Scholar 

  18. Davis HE, Mccorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21:133–46. https://doi.org/10.1038/s41579-022-00846-2.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601–15. https://doi.org/10.1038/s41591-021-01283-z.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Girum T, Lentiro K, Geremew M, Migora B, Shewamare S. Global strategies and effectiveness for COVID-19 prevention through contact tracing, screening, quarantine, and isolation: a systematic review. Trop Med Health. 2020;48:91. https://doi.org/10.1186/s41182-020-00285-w.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Girum T, Lentiro K, Geremew M, Migora B, Shewamare S, Shimbre MS. Optimal strategies for COVID-19 prevention from global evidence achieved through social distancing, stay at home, travel restriction and lockdown: a systematic review. Arch Public Health. 2021;79:150. https://doi.org/10.1186/s13690-021-00663-8.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Cai H, Liu G, Zhong J, et al. Immune checkpoints in viral infections. Viruses. 2020;12(9):1051. https://doi.org/10.3390/v12091051.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Lee N, Jeong S, Jeon K, Park MJ, Song W. Prognostic impacts of soluble immune checkpoint regulators and cytokines in patients with SARS-CoV-2 infection. Front Immunol. 2022;13:903419. https://doi.org/10.3389/fimmu.2022.903419.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Aghbash PS, Eslami N, Shamekh A, Entezari-Maleki T, Baghi HB. SARS-CoV-2 infection: the role of PD-1/PD-L1 and CTLA-4 axis. Life Sci. 2021;270:119124. https://doi.org/10.1016/j.lfs.2021.119124.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Gatto L, Franceschi E, Nunno VD, Brandes AA. Potential protective and therapeutic role of immune checkpoint inhibitors against viral infections and COVID-19. Immunotherapy. 2020;12:1111–4. https://doi.org/10.2217/imt-2020-0109.

    Article  CAS  PubMed  Google Scholar 

  26. Awadasseid A, Yin Q, Wu Y, Zhang W. Potential protective role of the anti-PD-1 blockade against SARS-CoV-2 infection. Biomed Pharmacother. 2021;142:111957. https://doi.org/10.1016/j.biopha.2021.111957.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Gambichler T, Reuther J, Scheel CH, Becker JC. On the use of immune checkpoint inhibitors in patients with viral infections including COVID-19. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2020-001145.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Shahbaz S, Xu L, Sligl W, et al. The quality of SARS-CoV-2-specific T cell functions differs in patients with mild/moderate versus severe disease, and T cells expressing coinhibitory receptors are highly activated. J Immunol. 2021;207:1099–111. https://doi.org/10.4049/jimmunol.2100446.

    Article  CAS  PubMed  Google Scholar 

  29. Bellesi S, Metafuni E, Hohaus S, et al. Increased CD95 (Fas) and PD-1 expression in peripheral blood T lymphocytes in COVID-19 patients. Br J Haematol. 2020;191:207–11. https://doi.org/10.1111/bjh.17034.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Herrmann M, Schulte S, Wildner NH, et al. Analysis of co-inhibitory receptor expression in COVID-19 infection compared to acute plasmodium falciparum malaria: LAG-3 and TIM-3 correlate with T cell activation and course of disease. Front Immunol. 2020;11:1870. https://doi.org/10.3389/fimmu.2020.01870.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Barnova M, Bobcakova A, Urdova V, et al. Inhibitory immune checkpoint molecules and exhaustion of T cells in COVID-19. Physiol Res. 2021;70:227–47. https://doi.org/10.33549/physiolres.934757.

    Article  CAS  Google Scholar 

  32. Oyewole-Said D, Konduri V, Vazquez-Perez J, Weldon SA, Levitt JM, Decker WK. Beyond T-cells: functional characterization of CTLA-4 expression in immune and non-immune cell types. Front Immunol. 2020;11:608024. https://doi.org/10.3389/fimmu.2020.608024.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Hou TZ, Qureshi OS, Wang CJ, et al. A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells. J Immunol. 2015;194:2148–59. https://doi.org/10.4049/jimmunol.1401876.

    Article  CAS  PubMed  Google Scholar 

  34. Yokosuka T, Kobayashi W, Takamatsu M, et al. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity. 2010;33:326–39. https://doi.org/10.1016/j.immuni.2010.09.006.

    Article  CAS  PubMed  Google Scholar 

  35. Guntermann C, Alexander DR. CTLA-4 suppresses proximal TCR signaling in resting human CD4(+) T cells by inhibiting ZAP-70 Tyr(319) phosphorylation: a potential role for tyrosine phosphatases. J Immunol. 2002;168:4420–9. https://doi.org/10.4049/jimmunol.168.9.4420.

    Article  CAS  PubMed  Google Scholar 

  36. Ruibal P, Oestereich L, Lüdtke A, et al. Unique human immune signature of Ebola virus disease in Guinea. Nature. 2016;533:100–4. https://doi.org/10.1038/nature17949.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Cao H, Zhang R, Zhang W. CTLA4 interferes with the HBV-specific T cell immune response (review). Int J Mol Med. 2018;42:703–12. https://doi.org/10.3892/ijmm.2018.3688.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Elahi S, Shahbaz S, Houston S. Selective upregulation of CTLA-4 on CD8+ T cells restricted by HLA-B*35Px renders them to an exhausted phenotype in HIV-1 infection. PLoS Pathog. 2020;16:e1008696. https://doi.org/10.1371/journal.ppat.1008696.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Kong Y, Wang Y, Wu X, et al. Storm of soluble immune checkpoints associated with disease severity of COVID-19. Signal Transduct Target Ther. 2020;5:192. https://doi.org/10.1038/s41392-020-00308-2.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Zahran AM, Nafady-Hego H, Rashad A, et al. Increased percentage of apoptotic and CTLA-4 (CD152) expressing cells in CD4+/CD8+ cells in COVID-19 patients. Medicine. 2022;101:e30650. https://doi.org/10.1097/md.0000000000030650.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Jeannet R, Daix T, Formento R, Feuillard J, François B. Severe COVID-19 is associated with deep and sustained multifaceted cellular immunosuppression. Intensive Care Med. 2020;46:1769–71. https://doi.org/10.1007/s00134-020-06127-x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Schub D, Klemis V, Schneitler S, et al. High levels of SARS-CoV-2-specific T cells with restricted functionality in severe courses of COVID-19. JCI Insight. 2020. https://doi.org/10.1172/jci.insight.142167.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Hou H, Zhang Y, Tang G, et al. Immunologic memory to SARS-CoV-2 in convalescent COVID-19 patients at 1 year postinfection. J Allergy Clin Immunol. 2021;148:1481–92. https://doi.org/10.1016/j.jaci.2021.09.008.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Al-Mterin MA, Alsalman A, Elkord E. Inhibitory immune checkpoint receptors and ligands as prognostic biomarkers in COVID-19 patients. Front Immunol. 2022;13:870283. https://doi.org/10.3389/fimmu.2022.870283.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Zhu X, Lang J. Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer. Oncotarget. 2017;8:97671. https://doi.org/10.18632/oncotarget.18311.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Rayati Damavandi A, Zolfaghari Baghbadorani P, Kardideh B, et al. The association of programmed death 1 gene polymorphisms of PD1.3 G/A and PD1.5 C/T with risk of COVID-19 in an Iranian population: a case-control study. Viral Immunol. 2022. https://doi.org/10.1089/vim.2022.0030.

    Article  PubMed  Google Scholar 

  47. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543–53. https://doi.org/10.1128/mcb.25.21.9543-9553.2005.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Haymaker C, Wu R, Bernatchez C, Radvanyi L. PD-1 and BTLA and CD8(+) T-cell “exhaustion” in cancer: “exercising” an alternative viewpoint. Oncoimmunology. 2012;1:735–8. https://doi.org/10.4161/onci.20823.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Davidson TB, Lee A, Hsu M, et al. Expression of PD-1 by T cells in malignant glioma patients reflects exhaustion and activation. Clin Cancer Res. 2019;25:1913–22. https://doi.org/10.1158/1078-0432.ccr-18-1176.

    Article  CAS  PubMed  Google Scholar 

  50. Saeidi A, Zandi K, Cheok YY, et al. T-cell exhaustion in chronic infections: reversing the state of exhaustion and reinvigorating optimal protective immune responses. Front Immunol. 2018;9:2569. https://doi.org/10.3389/fimmu.2018.02569.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Vali B, Jones RB, Sakhdari A, et al. HCV-specific T cells in HCV/HIV co-infection show elevated frequencies of dual Tim-3/PD-1 expression that correlate with liver disease progression. Eur J Immunol. 2010;40:2493–505. https://doi.org/10.1002/eji.201040340.

    Article  CAS  PubMed  Google Scholar 

  52. Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443:350–4. https://doi.org/10.1038/nature05115.

    Article  CAS  PubMed  Google Scholar 

  53. Hoogeveen RC, Robidoux MP, Schwarz T, et al. Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection. Gut. 2019;68:893–904. https://doi.org/10.1136/gutjnl-2018-316644.

    Article  CAS  PubMed  Google Scholar 

  54. Mahmoodpoor A, Hosseini M, Soltani-Zangbar S, et al. Reduction and exhausted features of T lymphocytes under serological changes, and prognostic factors in COVID-19 progression. Mol Immunol. 2021;138:121–7. https://doi.org/10.1016/j.molimm.2021.06.001.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Li M, Guo W, Dong Y, et al. Elevated exhaustion levels of NK and CD8(+) T cells as indicators for progression and prognosis of COVID-19 disease. Front Immunol. 2020;11:580237. https://doi.org/10.3389/fimmu.2020.580237.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Niedźwiedzka-Rystwej P, Majchrzak A, Aksak-Wąs B, et al. Programmed cell death-1/programmed cell death-1 ligand as prognostic markers of coronavirus disease 2019 severity. Cells. 2022;11(12):1978. https://doi.org/10.3390/cells11121978.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Moser D, Biere K, Han B, et al. COVID-19 impairs immune response to Candida albicans. Front Immunol. 2021;12:640644. https://doi.org/10.3389/fimmu.2021.640644.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Kulkarni-Munje A, Palkar S, Shrivastava S, Lalwani S, Mishra AC, Arankalle VA. Disease-duration based comparison of subsets of immune cells in SARS CoV-2 infected patients presenting with mild or severe symptoms identifies prognostic markers for severity. Immun Inflamm Dis. 2021;9:419–34. https://doi.org/10.1002/iid3.402.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Yang J, Zhong M, Zhang E, et al. Broad phenotypic alterations and potential dysfunction of lymphocytes in individuals clinically recovered from COVID-19. J Mol Cell Biol. 2021;13:197–209. https://doi.org/10.1093/jmcb/mjab014.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Varchetta S, Mele D, Oliviero B, et al. Unique immunological profile in patients with COVID-19. Cell Mol Immunol. 2021;18:604–12. https://doi.org/10.1038/s41423-020-00557-9.

    Article  CAS  PubMed  Google Scholar 

  61. Gutiérrez-Bautista JF, Rodriguez-Nicolas A, Rosales-Castillo A, et al. Negative clinical evolution in COVID-19 patients is frequently accompanied with an increased proportion of undifferentiated Th cells and a strong underrepresentation of the Th1 subset. Front Immunol. 2020;11:596553. https://doi.org/10.3389/fimmu.2020.596553.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Breton G, Mendoza P, Hägglöf T, et al. Persistent cellular immunity to SARS-CoV-2 infection. J Exp Med. 2021;218(4):e20202515. https://doi.org/10.1084/jem.20202515.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Glynne P, Tahmasebi N, Gant V, Gupta R. Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines. J Investig Med. 2022;70:61–7. https://doi.org/10.1136/jim-2021-002051.

    Article  PubMed  Google Scholar 

  64. Zhao L, Cheng S, Fan L, Zhang B, Xu S. TIM-3: an update on immunotherapy. Int Immunopharmacol. 2021;99:107933. https://doi.org/10.1016/j.intimp.2021.107933.

    Article  CAS  PubMed  Google Scholar 

  65. Zhao L, Yu G, Han Q, Cui C, Zhang B. TIM-3: an emerging target in the liver diseases. Scand J Immunol. 2020;91:e12825. https://doi.org/10.1111/sji.12825.

    Article  PubMed  Google Scholar 

  66. Sakuishi K, Jayaraman P, Behar SM, Anderson AC, Kuchroo VK. Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol. 2011;32:345–9. https://doi.org/10.1016/j.it.2011.05.003.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Tang D, Lotze MT. Tumor immunity times out: TIM-3 and HMGB1. Nat Immunol. 2012;13:808–10. https://doi.org/10.1038/ni.2396.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Huang YH, Zhu C, Kondo Y, et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature. 2015;517:386–90. https://doi.org/10.1038/nature13848.

    Article  CAS  PubMed  Google Scholar 

  69. Fazeli G, Beer KB, Geisenhof M, et al. Loss of the major phosphatidylserine or phosphatidylethanolamine flippases differentially affect phagocytosis. Front Cell Dev Biol. 2020;8:648. https://doi.org/10.3389/fcell.2020.00648.

    Article  PubMed Central  PubMed  Google Scholar 

  70. Sordi R, Bet ÂC, Della Justina AM, Ramos GC, Assreuy J. The apoptosis clearance signal phosphatidylserine inhibits leukocyte migration and promotes inflammation resolution in vivo. Eur J Pharmacol. 2020;877:173095. https://doi.org/10.1016/j.ejphar.2020.173095.

    Article  CAS  PubMed  Google Scholar 

  71. Jin HT, Anderson AC, Tan WG, et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA. 2010;107:14733–8. https://doi.org/10.1073/pnas.1009731107.

    Article  PubMed Central  PubMed  Google Scholar 

  72. Jones RB, Ndhlovu LC, Barbour JD, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205:2763–79. https://doi.org/10.1084/jem.20081398.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Mcmahan RH, Golden-Mason L, Nishimura MI, et al. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J Clin Invest. 2010;120:4546–57. https://doi.org/10.1172/jci43127.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Uranga-Murillo I, Morte E, Hidalgo S, et al. Integrated analysis of circulating immune cellular and soluble mediators reveals specific COVID19 signatures at hospital admission with utility for prediction of clinical outcomes. Theranostics. 2022;12:290–306. https://doi.org/10.7150/thno.63463.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Saeedifar AM, Ghorban K, Ganji A, et al. Evaluation of Tcell exhaustion based on the expression of EOMES, Tbet and co-inhibitory receptors in severe and non-severe covid-19 patients. Gene Rep. 2023;31:101747. https://doi.org/10.1016/j.genrep.2023.101747.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Shahbazi M, Moulana Z, Sepidarkish M, et al. Pronounce expression of Tim-3 and CD39 but not PD1 defines CD8 T cells in critical Covid-19 patients. Microb Pathog. 2021;153:104779. https://doi.org/10.1016/j.micpath.2021.104779.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Diao B, Wang C, Tan Y, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol. 2020;11:827. https://doi.org/10.3389/fimmu.2020.00827.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Bobcakova A, Petriskova J, Vysehradsky R, et al. Immune profile in patients with COVID-19: lymphocytes exhaustion markers in relationship to clinical outcome. Front Cell Infect Microbiol. 2021;11:646688. https://doi.org/10.3389/fcimb.2021.646688.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Bonifacius A, Tischer-Zimmermann S, Dragon AC, et al. COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses. Immunity. 2021;54:340–54. https://doi.org/10.1016/j.immuni.2021.01.008.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Ueland T, Heggelund L, Lind A, et al. Elevated plasma sTIM-3 levels in patients with severe COVID-19. J Allergy Clin Immunol. 2021;147:92–8. https://doi.org/10.1016/j.jaci.2020.09.007.

    Article  CAS  PubMed  Google Scholar 

  81. Chavez-Galan L, Ruiz A, Martinez-Espinosa K, et al. Circulating levels of PD-L1, TIM-3 and MMP-7 are promising biomarkers to differentiate COVID-19 patients that require invasive mechanical ventilation. Biomolecules. 2022;12(3):445. https://doi.org/10.3390/biom12030445.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Joller N, Kuchroo VK. Tim-3, lag-3, and TIGIT. Curr Top Microbiol Immunol. 2017;410:127–56. https://doi.org/10.1007/82_2017_62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Maruhashi T, Okazaki IM, Sugiura D, et al. LAG-3 inhibits the activation of CD4(+) T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat Immunol. 2018;19:1415–26. https://doi.org/10.1038/s41590-018-0217-9.

    Article  CAS  PubMed  Google Scholar 

  84. Maruhashi T, Sugiura D, Okazaki IM, Okazaki T. LAG-3: from molecular functions to clinical applications. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2020-001014.

    Article  PubMed Central  PubMed  Google Scholar 

  85. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37. https://doi.org/10.1038/ni.1679.

    Article  CAS  PubMed  Google Scholar 

  86. Ye B, Li X, Dong Y, et al. Increasing LAG-3 expression suppresses T-cell function in chronic hepatitis B: a balance between immunity strength and liver injury extent. Medicine. 2017;96:e5275. https://doi.org/10.1097/md.0000000000005275.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Rendeiro AF, Casano J, Vorkas CK, et al. Profiling of immune dysfunction in COVID-19 patients allows early prediction of disease progression. Life Sci Alliance. 2021. https://doi.org/10.26508/lsa.202000955.

    Article  PubMed  Google Scholar 

  88. Deng Z, Zheng Y, Cai P, Zheng Z. The role of B and T lymphocyte attenuator in respiratory system diseases. Front Immunol. 2021;12:635623. https://doi.org/10.3389/fimmu.2021.635623.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Kobayashi Y, Iwata A, Suzuki K, et al. B and T lymphocyte attenuator inhibits LPS-induced endotoxic shock by suppressing toll-like receptor 4 signaling in innate immune cells. Proc Natl Acad Sci USA. 2013;110:5121–6. https://doi.org/10.1073/pnas.1222093110.

    Article  PubMed Central  PubMed  Google Scholar 

  90. Miller ML, Sun Y, Fu YX. Cutting edge: B and T lymphocyte attenuator signaling on NKT cells inhibits cytokine release and tissue injury in early immune responses. J Immunol. 2009;183:32–6. https://doi.org/10.4049/jimmunol.0900690.

    Article  CAS  PubMed  Google Scholar 

  91. Serriari NE, Gondois-Rey F, Guillaume Y, et al. B and T lymphocyte attenuator is highly expressed on CMV-specific T cells during infection and regulates their function. J Immunol. 2010;185:3140–8. https://doi.org/10.4049/jimmunol.0902487.

    Article  CAS  PubMed  Google Scholar 

  92. Flynn R, Hutchinson T, Murphy KM, Ware CF, Croft M, Salek-Ardakani S. CD8 T cell memory to a viral pathogen requires trans cosignaling between HVEM and BTLA. PLoS ONE. 2013;8:e77991. https://doi.org/10.1371/journal.pone.0077991.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Schultheiß C, Paschold L, Simnica D, et al. Next-generation sequencing of T and B cell receptor repertoires from COVID-19 patients showed signatures associated with severity of disease. Immunity. 2020;53:442–55. https://doi.org/10.1016/j.immuni.2020.06.024.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Saheb Sharif-Askari N, Saheb Sharif-Askari F, Mdkhana B, et al. Enhanced expression of immune checkpoint receptors during SARS-CoV-2 viral infection. Mol Ther Methods Clin Dev. 2021;20:109–21. https://doi.org/10.1016/j.omtm.2020.11.002.

    Article  CAS  PubMed  Google Scholar 

  95. Cai G, Anumanthan A, Brown JA, Greenfield EA, Zhu B, Freeman GJ. CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator. Nat Immunol. 2008;9:176–85. https://doi.org/10.1038/ni1554.

    Article  CAS  PubMed  Google Scholar 

  96. Kim TJ, Park G, Kim J, et al. CD160 serves as a negative regulator of NKT cells in acute hepatic injury. Nat Commun. 2019;10:3258. https://doi.org/10.1038/s41467-019-10320-y.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Le Bouteiller P, Barakonyi A, Giustiniani J, et al. Engagement of CD160 receptor by HLA-C is a triggering mechanism used by circulating natural killer (NK) cells to mediate cytotoxicity. Proc Natl Acad Sci USA. 2002;99:16963–8. https://doi.org/10.1073/pnas.012681099.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Barakonyi A, Rabot M, Marie-Cardine A, et al. Cutting edge: engagement of CD160 by its HLA-C physiological ligand triggers a unique cytokine profile secretion in the cytotoxic peripheral blood NK cell subset. J Immunol. 2004;173:5349–54. https://doi.org/10.4049/jimmunol.173.9.5349.

    Article  CAS  PubMed  Google Scholar 

  99. Bortolotti D, Gentili V, Rizzo S, et al. Increased sHLA-G is associated with improved COVID-19 outcome and reduced neutrophil adhesion. Viruses. 2021;13(9):1855. https://doi.org/10.3390/v13091855.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Zhang L, Zhang A, Xu J, et al. CD160 plays a protective role during chronic infection by enhancing both functionalities and proliferative capacity of CD8+ T cells. Front Immunol. 2020;11:2188. https://doi.org/10.3389/fimmu.2020.02188.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Sun Z, Li Y, Zhang Z, et al. CD160 promotes NK cell functions by upregulating glucose metabolism and negatively correlates with HIV disease progression. Front Immunol. 2022;13:854432. https://doi.org/10.3389/fimmu.2022.854432.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Peretz Y, He Z, Shi Y, et al. CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction. PLoS Pathog. 2012;8:e1002840. https://doi.org/10.1371/journal.ppat.1002840.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Zhang JY, Wang XM, Xing X, et al. Single-cell landscape of immunological responses in patients with COVID-19. Nat Immunol. 2020;21:1107–18. https://doi.org/10.1038/s41590-020-0762-x.

    Article  CAS  PubMed  Google Scholar 

  104. Schwertner B, Lindner G, Toledo Stauner C, et al. Nectin-1 expression correlates with the susceptibility of malignant melanoma to oncolytic herpes simplex virus in vitro and in vivo. Cancers. 2021;13(12):3058. https://doi.org/10.3390/cancers13123058.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Steinberg MW, Cheung TC, Ware CF. The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunol Rev. 2011;244:169–87. https://doi.org/10.1111/j.1600-065X.2011.01064.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Liu W, Chou TF, Garrett-Thomson SC, et al. HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160. J Exp Med. 2021;218:e20211112. https://doi.org/10.1084/jem.20211112.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Sedý JR, Spear PG, Ware CF. Cross-regulation between herpesviruses and the TNF superfamily members. Nat Rev Immunol. 2008;8:861–73. https://doi.org/10.1038/nri2434.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Montgomery RI, Warner MS, Lum BJ, Spear PG. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell. 1996;87:427–36. https://doi.org/10.1016/s0092-8674(00)81363-x.

    Article  CAS  PubMed  Google Scholar 

  109. Lozano-Rodríguez R, Terrón-Arcos V, López R, et al. Differential immune checkpoint and Ig-like V-type receptor profiles in COVID-19: associations with severity and treatment. J Clin Med. 2022;11(12):3287. https://doi.org/10.3390/jcm11123287.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Perlin DS, Zafir-Lavie I, Roadcap L, Raines S, Ware CF, Neil GA. Levels of the TNF-related cytokine LIGHT increase in hospitalized COVID-19 patients with cytokine release syndrome and ARDS. MSphere. 2020;5(4):10–1128. https://doi.org/10.1128/mSphere.00699-20.

    Article  Google Scholar 

  111. Arunachalam PS, Wimmers F, Mok CKP, et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science. 2020;369:1210–20. https://doi.org/10.1126/science.abc6261.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  112. Carvalheiro T, Garcia S, Pascoal Ramos MI, et al. Leukocyte associated immunoglobulin like receptor 1 regulation and function on monocytes and dendritic cells during inflammation. Front Immunol. 2020;11:1793. https://doi.org/10.3389/fimmu.2020.01793.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Olde Nordkamp MJ, Van Eijk M, Urbanus RT, Bont L, Haagsman HP, Meyaard L. Leukocyte-associated Ig-like receptor-1 is a novel inhibitory receptor for surfactant protein D. J Leukoc Biol. 2014;96:105–11. https://doi.org/10.1189/jlb.3AB0213-092RR.

    Article  CAS  PubMed  Google Scholar 

  114. Son M, Santiago-Schwarz F, Al-Abed Y, Diamond B. C1q limits dendritic cell differentiation and activation by engaging LAIR-1. Proc Natl Acad Sci USA. 2012;109:E3160–7. https://doi.org/10.1073/pnas.1212753109.

    Article  PubMed Central  PubMed  Google Scholar 

  115. Maasho K, Masilamani M, Valas R, Basu S, Coligan JE, Borrego F. The inhibitory leukocyte-associated Ig-like receptor-1 (LAIR-1) is expressed at high levels by human naive T cells and inhibits TCR mediated activation. Mol Immunol. 2005;42:1521–30. https://doi.org/10.1016/j.molimm.2005.01.004.

    Article  CAS  PubMed  Google Scholar 

  116. Meyaard L, Adema GJ, Chang C, et al. LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes. Immunity. 1997;7:283–90. https://doi.org/10.1016/s1074-7613(00)80530-0.

    Article  CAS  PubMed  Google Scholar 

  117. Merlo A, Tenca C, Fais F, et al. Inhibitory receptors CD85j, LAIR-1, and CD152 down-regulate immunoglobulin and cytokine production by human B lymphocytes. Clin Diagn Lab Immunol. 2005;12:705–12. https://doi.org/10.1128/cdli.12.6.705-712.2005.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  118. Son M, Diamond B. C1q-mediated repression of human monocytes is regulated by leukocyte-associated Ig-like receptor 1 (LAIR-1). Mol Med. 2015;20:559–68. https://doi.org/10.2119/molmed.2014.00185.

    Article  PubMed Central  PubMed  Google Scholar 

  119. Altable M, De La Serna JM. Protection against COVID-19 in African population: immunology, genetics, and malaria clues for therapeutic targets. Virus Res. 2021;299:198347. https://doi.org/10.1016/j.virusres.2021.198347.

    Article  CAS  PubMed  Google Scholar 

  120. Bonaccorsi I, Cantoni C, Carrega P, et al. The immune inhibitory receptor LAIR-1 is highly expressed by plasmacytoid dendritic cells and acts complementary with NKp44 to control IFNα production. PLoS ONE. 2010;5:e15080. https://doi.org/10.1371/journal.pone.0015080.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  121. Jansen CA, Cruijsen CW, De Ruiter T, et al. Regulated expression of the inhibitory receptor LAIR-1 on human peripheral T cells during T cell activation and differentiation. Eur J Immunol. 2007;37:914–24. https://doi.org/10.1002/eji.200636678.

    Article  CAS  PubMed  Google Scholar 

  122. Aoukaty A, Lee IF, Wu J, Tan R. Chronic active Epstein–Barr virus infection associated with low expression of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) on natural killer cells. J Clin Immunol. 2003;23:141–5. https://doi.org/10.1023/a:1022580929226.

    Article  CAS  PubMed  Google Scholar 

  123. Gu Y, Bi Y, Wei H, et al. Expression and clinical significance of inhibitory receptor Leukocyte-associated immunoglobulin-like receptor-1 on peripheral blood T cells of chronic hepatitis B patients: a cross-sectional study. Medicine. 2021;100:e26667. https://doi.org/10.1097/md.0000000000026667.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  124. Seery V, Raiden SC, Algieri SC, et al. Blood neutrophils from children with COVID-19 exhibit both inflammatory and anti-inflammatory markers. EBioMedicine. 2021;67:103357. https://doi.org/10.1016/j.ebiom.2021.103357.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Van Der Wijst MGP, Vazquez SE, Hartoularos GC, et al. Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19. Sci Transl Med. 2021;13:eabh2624. https://doi.org/10.1126/scitranslmed.abh2624.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  126. Wang Y, Zhong H, Xie X, et al. Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection. Proc Natl Acad Sci USA. 2015;112:E3883–92. https://doi.org/10.1073/pnas.1501662112.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  127. Sun L, Gang X, Li Z, et al. Advances in understanding the roles of CD244 (SLAMF4) in immune regulation and associated diseases. Front Immunol. 2021;12:648182. https://doi.org/10.3389/fimmu.2021.648182.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. De Sanctis JB, Garmendia JV, Hajdúch M. Overview of memory NK cells in viral infections: possible role in SARS-CoV-2 infection. Immuno. 2022;2:52–67. https://doi.org/10.3390/immuno2010005.

    Article  Google Scholar 

  129. Menner AJ, Rauch KS, Aichele P, Pircher H, Schachtrup C, Schachtrup K. Id3 controls cell death of 2B4+ virus-specific CD8+ T cells in chronic viral infection. J Immunol. 2015;195:2103–14. https://doi.org/10.4049/jimmunol.1402607.

    Article  CAS  PubMed  Google Scholar 

  130. Ye B, Liu X, Li X, Kong H, Tian L, Chen Y. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis. 2015;6:e1694. https://doi.org/10.1038/cddis.2015.42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  131. Buggert M, Tauriainen J, Yamamoto T, et al. T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog. 2014;10:e1004251. https://doi.org/10.1371/journal.ppat.1004251.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. Raziorrouh B, Schraut W, Gerlach T, et al. The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell function. Hepatology. 2010;52:1934–47. https://doi.org/10.1002/hep.23936.

    Article  CAS  PubMed  Google Scholar 

  133. Enose-Akahata Y, Matsuura E, Oh U, Jacobson S. High expression of CD244 and SAP regulated CD8 T cell responses of patients with HTLV-I associated neurologic disease. PLoS Pathog. 2009;5:e1000682. https://doi.org/10.1371/journal.ppat.1000682.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  134. Cotugno N, Ruggiero A, Bonfante F, et al. Virological and immunological features of SARS-CoV-2-infected children who develop neutralizing antibodies. Cell Rep. 2021;34:108852. https://doi.org/10.1016/j.celrep.2021.108852.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  135. Yu J, Mao HC, Wei M, et al. CD94 surface density identifies a functional intermediary between the CD56bright and CD56dim human NK-cell subsets. Blood. 2010;115:274–81. https://doi.org/10.1182/blood-2009-04-215491.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  136. Vance RE, Jamieson AM, Cado D, Raulet DH. Implications of CD94 deficiency and monoallelic NKG2A expression for natural killer cell development and repertoire formation. Proc Natl Acad Sci USA. 2002;99:868–73. https://doi.org/10.1073/pnas.022500599.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Bortolotti D, Gentili V, Rizzo S, Rotola A, Rizzo R. SARS-CoV-2 spike 1 protein controls natural killer cell activation via the HLA-E/NKG2A pathway. Cells. 2020;9(9):1975. https://doi.org/10.3390/cells9091975.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Bastidas-Legarda LY, Khakoo SI. Conserved and variable natural killer cell receptors: diverse approaches to viral infections. Immunology. 2019;156:319–28. https://doi.org/10.1111/imm.13039.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Wang X, Xiong H, Ning Z. Implications of NKG2A in immunity and immune-mediated diseases. Front Immunol. 2022;13:960852. https://doi.org/10.3389/fimmu.2022.960852.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Li F, Wei H, Wei H, et al. Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice. Gastroenterology. 2013;144:392–401. https://doi.org/10.1053/j.gastro.2012.10.039.

    Article  CAS  PubMed  Google Scholar 

  141. Haanen JB, Cerundolo V. NKG2A, a New Kid on the immune checkpoint block. Cell. 2018;175:1720–2. https://doi.org/10.1016/j.cell.2018.11.048.

    Article  CAS  PubMed  Google Scholar 

  142. Nattermann J, Nischalke HD, Hofmeister V, et al. The HLA-A2 restricted T cell epitope HCV core 35–44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells. Am J Pathol. 2005;166:443–53. https://doi.org/10.1016/s0002-9440(10)62267-5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Lee G, Schauner R, Burke J, et al. NK cells from COVID-19 positive patients exhibit enhanced cytotoxic activity upon NKG2A and KIR2DL1 blockade. Front Immunol. 2023;14:1022890. https://doi.org/10.3389/fimmu.2023.1022890.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  144. Moll-Bernardes R, Fortier SC, Sousa AS, et al. NKG2A expression among CD8 cells is associated with COVID-19 progression in hypertensive patients: insights from the BRACE CORONA randomized trial. J Clin Med. 2022;11(13):3713. https://doi.org/10.3390/jcm11133713.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  145. 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. https://doi.org/10.1016/j.mehy.2020.109777.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  146. Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 2020;17:533–5. https://doi.org/10.1038/s41423-020-0402-2.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  147. Flies DB, Wang S, Xu H, Chen L. Cutting edge: a monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models. J Immunol. 2011;187:1537–41. https://doi.org/10.4049/jimmunol.1100660.

    Article  CAS  PubMed  Google Scholar 

  148. Eltanbouly MA, Zhao Y, Schaafsma E, et al. VISTA: a target to manage the innate cytokine storm. Front Immunol. 2020;11:595950. https://doi.org/10.3389/fimmu.2020.595950.

    Article  CAS  PubMed  Google Scholar 

  149. Shahbaz S, Dunsmore G, Koleva P, Xu L, Houston S, Elahi S. Galectin-9 and VISTA expression define terminally exhausted T cells in HIV-1 infection. J Immunol. 2020;204:2474–91. https://doi.org/10.4049/jimmunol.1901481.

    Article  CAS  PubMed  Google Scholar 

  150. Lines JL, Pantazi E, Mak J, et al. VISTA is an immune checkpoint molecule for human T cells. Cancer Res. 2014;74:1924–32. https://doi.org/10.1158/0008-5472.can-13-1504.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  151. Huang X, Zhang X, Li E, et al. VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol. 2020;13:83. https://doi.org/10.1186/s13045-020-00917-y.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  152. Slater BT, Han X, Chen L, Xiong Y. Structural insight into T cell coinhibition by PD-1H (VISTA). Proc Natl Acad Sci USA. 2020;117:1648–57. https://doi.org/10.1073/pnas.1908711117.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  153. Bharaj P, Chahar HS, Alozie OK, et al. Characterization of programmed death-1 homologue-1 (PD-1H) expression and function in normal and HIV infected individuals. PLoS ONE. 2014;9:e109103. https://doi.org/10.1371/journal.pone.0109103.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  154. Seeds RE, Mukhopadhyay S, Jones IM, Gordon S, Miller JL. The role of myeloid receptors on murine plasmacytoid dendritic cells in induction of type I interferon. Int Immunopharmacol. 2011;11:794–801. https://doi.org/10.1016/j.intimp.2011.01.013.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Vaine CA, Soberman RJ. The CD200-CD200R1 inhibitory signaling pathway: immune regulation and host-pathogen interactions. Adv Immunol. 2014;121:191–211. https://doi.org/10.1016/b978-0-12-800100-4.00005-2.

    Article  CAS  PubMed  Google Scholar 

  156. Barclay AN, Wright GJ, Brooke G, Brown MH. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol. 2002;23:285–90. https://doi.org/10.1016/s1471-4906(02)02223-8.

    Article  CAS  PubMed  Google Scholar 

  157. Kotwica-Mojzych K, Jodłowska-Jędrych B, Mojzych M. CD200: CD200R interactions and their importance in immunoregulation. Int J Mol Sci. 2021;22(4):1602. https://doi.org/10.3390/ijms22041602.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  158. Koning N, Van Eijk M, Pouwels W, et al. Expression of the inhibitory CD200 receptor is associated with alternative macrophage activation. J Innate Immun. 2010;2:195–200. https://doi.org/10.1159/000252803.

    Article  CAS  PubMed  Google Scholar 

  159. Ceribelli A, Motta F, De Santis M, et al. Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy. J Autoimmun. 2020;109:102442. https://doi.org/10.1016/j.jaut.2020.102442.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Snelgrove RJ, Goulding J, Didierlaurent AM, et al. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nat Immunol. 2008;9:1074–83. https://doi.org/10.1038/ni.1637.

    Article  CAS  PubMed  Google Scholar 

  161. Karnam G, Rygiel TP, Raaben M, et al. CD200 receptor controls sex-specific TLR7 responses to viral infection. PLoS Pathog. 2012;8:e1002710. https://doi.org/10.1371/journal.ppat.1002710.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  162. Chen Z, Ma X, Zhang J, Hu J, Gorczynski RM. Alternative splicing of CD200 is regulated by an exonic splicing enhancer and SF2/ASF. Nucleic Acids Res. 2010;38:6684–96. https://doi.org/10.1093/nar/gkq554.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  163. Rygiel TP, Rijkers ES, De Ruiter T, et al. Lack of CD200 enhances pathological T cell responses during influenza infection. J Immunol. 2009;183:1990–6. https://doi.org/10.4049/jimmunol.0900252.

    Article  CAS  PubMed  Google Scholar 

  164. Mukhopadhyay S, Plüddemann A, Hoe JC, et al. Immune inhibitory ligand CD200 induction by TLRs and NLRs limits macrophage activation to protect the host from meningococcal septicemia. Cell Host Microbe. 2010;8:236–47. https://doi.org/10.1016/j.chom.2010.08.005.

    Article  CAS  PubMed  Google Scholar 

  165. Forouzani-Haghighi B, Rezvani A, Vazin A. Immune targeted therapies for COVID-19 infection: a narrative review. Iran J Med Sci. 2022;47:291. https://doi.org/10.30476/ijms.2021.91614.2277.

    Article  PubMed Central  PubMed  Google Scholar 

  166. Yu X, Harden K, Gonzalez LC, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009;10:48–57. https://doi.org/10.1038/ni.1674.

    Article  CAS  PubMed  Google Scholar 

  167. Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA. 2009;106:17858–63. https://doi.org/10.1073/pnas.0903474106.

    Article  PubMed Central  PubMed  Google Scholar 

  168. Harjunpää H, Guillerey C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2020;200:108–19. https://doi.org/10.1111/cei.13407.

    Article  PubMed  Google Scholar 

  169. Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26:923–37. https://doi.org/10.1016/j.ccell.2014.10.018.

    Article  CAS  PubMed  Google Scholar 

  170. Zheng HY, Zhang M, Yang CX, 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;17:541–3. https://doi.org/10.1038/s41423-020-0401-3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  171. Mazzoni A, Maggi L, Capone M, et al. Cell-mediated and humoral adaptive immune responses to SARS-CoV-2 are lower in asymptomatic than symptomatic COVID-19 patients. Eur J Immunol. 2020;50:2013–24. https://doi.org/10.1002/eji.202048915.

    Article  CAS  PubMed  Google Scholar 

  172. Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer. Nat Med. 2020;26:1218–23. https://doi.org/10.1038/s41591-020-0979-0.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  173. Lovly CM, Boyd KL, Gonzalez-Ericsson PI, et al. Rapidly fatal pneumonitis from immunotherapy and concurrent SARS-CoV-2 infection in a patient with newly diagnosed lung cancer. MedRxiv. 2020. https://doi.org/10.1101/2020.04.29.20085738.

    Article  PubMed Central  PubMed  Google Scholar 

  174. Moritz RKC, Gutzmer R, Zimmer L, et al. SARS-CoV-2 infections in melanoma patients treated with PD-1 inhibitors: a survey of the German ADOREG melanoma registry. Eur J Cancer. 2021;144:382–5. https://doi.org/10.1016/j.ejca.2020.11.015.

    Article  CAS  PubMed  Google Scholar 

  175. Ochoa Gonzalez S, Abers MS, Rosen LB, et al. Management and outcome of COVID-19 in CTLA-4 insufficiency. Blood Adv. 2023. https://doi.org/10.1182/bloodadvances.2023010105.

    Article  Google Scholar 

  176. Bui AN, Tyan K, Giobbie-Hurder A, et al. Impact of COVID-19 on patients with cancer receiving immune checkpoint inhibitors. J Immunother Precis Oncol. 2021;4:35–44. https://doi.org/10.36401/jipo-20-34.

    Article  PubMed Central  PubMed  Google Scholar 

  177. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1 blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov. 2020;10:1121–8. https://doi.org/10.1158/2159-8290.cd-20-0596.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all individuals who participated in the studies cited in this article. All the figures were designed using Biorender online software, so we are very grateful to the Biorender team.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

    Ensiye Torki, Arezou Gharezade, Shima Sheikhi & Hamed Fouladseresht

  2. Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Mehrnoosh Doroudchi

  3. Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

    Davood Mansury

  4. Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus

    Mark J. M. Sullman

  5. Department of Social Sciences, University of Nicosia, Nicosia, Cyprus

    Mark J. M. Sullman

Authors
  1. Ensiye Torki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arezou Gharezade
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehrnoosh Doroudchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shima Sheikhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Davood Mansury
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark J. M. Sullman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hamed Fouladseresht
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ET, AG, MD, SS, DM, and HF wrote and reviewed the manuscript. ET and HF designed the figures. HF, MS, and MD reviewed the manuscript and provided suggestions. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Hamed Fouladseresht.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Torki, E., Gharezade, A., Doroudchi, M. et al. The kinetics of inhibitory immune checkpoints during and post-COVID-19: the knowns and unknowns. Clin Exp Med 23, 3299–3319 (2023). https://doi.org/10.1007/s10238-023-01188-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-023-01188-w

Keywords

Search

Navigation