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Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent
Alessio Mazzoni, … , Francesco Annunziato, Lorenzo Cosmi
Alessio Mazzoni, … , Francesco Annunziato, Lorenzo Cosmi
Published May 28, 2020
Citation Information: J Clin Invest. 2020;130(9):4694-4703. https://doi.org/10.1172/JCI138554.
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Clinical Medicine Immunology Infectious disease

Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent

Abstract

BACKGROUND Coronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Antiviral immune response is crucial to achieve pathogen clearance; however, in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options.METHODS We performed a flow cytometric characterization of immune cell subsets from 30 patients with COVID-19 and correlated these data with clinical outcomes.RESULTS Patients with COVID-19 showed decreased numbers of circulating T, B, and NK cells and exhibited a skewing of CD8+ T cells toward a terminally differentiated/senescent phenotype. In agreement, CD4+ T and CD8+ T, but also NK cells, displayed reduced antiviral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in patients with COVID-19, particularly in those who required intensive care. The latter group of patients also showed increased serum IL-6 levels that inversely correlated to the frequency of granzyme A–expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells.CONCLUSION The association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms.FUNDING This study was supported by funds from the Department of Experimental and Clinical Medicine of University of Florence (the ex-60% fund and the “Excellence Departments 2018–2022 Project”) derived from Ministero dell’Istruzione, dell’Università e della Ricerca (Italy).

Authors

Alessio Mazzoni, Lorenzo Salvati, Laura Maggi, Manuela Capone, Anna Vanni, Michele Spinicci, Jessica Mencarini, Roberto Caporale, Benedetta Peruzzi, Alberto Antonelli, Michele Trotta, Lorenzo Zammarchi, Luca Ciani, Leonardo Gori, Chiara Lazzeri, Andrea Matucci, Alessandra Vultaggio, Oliviero Rossi, Fabio Almerigogna, Paola Parronchi, Paolo Fontanari, Federico Lavorini, Adriano Peris, Gian Maria Rossolini, Alessandro Bartoloni, Sergio Romagnani, Francesco Liotta, Francesco Annunziato, Lorenzo Cosmi

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Implication of HLA-G/receptor signaling in impairment of immune responses in COVID-19 patients

Submitter: Wei-Hua Yan | yanwhcom@yahoo.com

Authors: Hui-Hui Xu, Aifen Lin, Wei-Hua Yan

Wenzhou Medical University

Published July 9, 2020

Pandemic COVID-19 has become a serious public health concern. Host innate and adaptive immune responses are indispensable to counteract virus infection and disease progression (1). Unfortunately, decreased number and abnormal function of various immune cells in COVID-19 patients have been frequently observed, which is associated with severity and/or poor outcome of COVID-19 patients (2).

Human leukocyte antigen-G (HLA-G) is a potent immune inhibitory mediator via its receptor signaling (3). HLA-G binding to its receptors immunoglobulin-like transcripts 2 (ILT-2) and ILT-4 can impair immune cell T cell and B cell proliferation, antigen presenting dendritic cell maturation, T cell, B cell and NK cell cytotoxicity and anti-viral cytokine secretion, and induce generation of regulatory T cells and MDSCs or M2 type macrophages. Moreover, HLA-G/CD8 binding can induce CD8+ T cell apoptosis through the Fas/FasL signaling pathway, and HLA-G/KIR2DL4 interactions can induce the senescence of NK cells (4, 5). HLA-G can be up-regulated by various virus infection such as SARS coronavirus, HIV and HCMV, and HLA-G/receptor signaling pathway plays comprehensive immune suppressive roles favoring virus immune evasion and related disease progression (6, 7). However, information on HLA-G and its receptors expression on immune cells in COVID-19 patients is very limited. In a patient suffering from critical COVID-19 pneumonia to convalescence, our previous study revealed the dynamics of HLA-G and receptors ILT2, ILT4 and KIR2DL4 expression on peripheral T, B and monocytes. Our findings indicated that SARS-CoV-2 infection might be involved in regulation of HLA-G and its receptor expression (8).

Recently, Mazzoni et al. (9) reported that decreased number and impaired function of lymphocyte subsets in COVID-19 patients. In this study, decreased counts of peripheral T lymphocytes and CD4+ T cells, CD8+ T cells and CD56+ NKT subpopulations, B lymphocytes and NK cells. Much higher frequencies of senescent phenotype TEMRA+ CD57+ CD8+ T cells but less anti-viral cytokine production and cytotoxicity from CD4+ and CD8+ T cells and NK cells have been observed in COVID-19 patients. Moreover, higher IL-6 levels were presented in ICU-treated patients, which was inversely related to the frequency of granzyme-expressing cytotoxic NK cells.

As above outlined knowledge, we speculated that HLA-G expression on immune cells could be up-regulated by SARS-CoV-2 infection. Consequently, HLA-G/receptor signaling pathway could be a mechanism involved in the impairment of both immune cell proliferation and cytotoxicity in COVID-19 patients. On this basis, we hypothesized that HLA-G/receptor signaling intervention could be a potential treatment for SARS-CoV-2 infection.

 

REFERENCES

  1. Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20(5):269-270.
  2. Azkur AK, et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 2020. doi: 10.1111/all.14364. Online ahead of print
  3. Carosella ED, et al. HLA-G: An Immune Checkpoint Molecule. Adv Immunol. 2015;127:33-144.
  4. Lin A, Yan WH. Heterogeneity of HLA-G Expression in Cancers: Facing the Challenges. Front Immunol. 2018; 9:2164.
  5. Rajagopalan S. HLA-G-mediated NK Cell Senescence Promotes Vascular Remodeling: Implications for Reproduction. Cell Mol Immunol. 2014; 11(5):460-6.
  6. Josset L, et al. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. MBio 2013; 4: e00165–13.
  7. Amiot L, Vu N, Samson M. Biology of the immunomodulatory molecule HLA-G in human liver diseases. J Hepatol. 2015; 62(6):1430-7.
  8. Zhang S, et al. Dynamics of peripheral immune cells and their HLA-G and receptor expressions in a patient suffering from critical COVID-19 pneumonia to convalescence. Clin Transl Immunology 2020; 9(5):e1128.
  9. Mazzoni A, et al. Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent. J Clin Invest. 2020. doi: 10.1172/JCI138554.

 

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