Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Nov 11

PMID 36359845

Authors

Marta Di Simone

Anna Maria Corsale

Elena Lo Presti

Nicola Scichilone

Carmela Picone

Lydia Giannitrapani

Francesco Dieli

Serena Meraviglia

Affiliations

Soon will be listed here.

Abstract

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients.

References

McAuley D, Charles P, Papazian L . Statins in patients with sepsis and ARDS: is it over? We are not sure. Intensive Care Med. 2016; 43(5):677-679. DOI: 10.1007/s00134-016-4454-9. View

Corsale A, Di Simone M, Lo Presti E, Picone C, Dieli F, Meraviglia S . Metabolic Changes in Tumor Microenvironment: How Could They Affect γδ T Cells Functions?. Cells. 2021; 10(11). PMC: 8616133. DOI: 10.3390/cells10112896. View

Oesterle A, Laufs U, Liao J . Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res. 2017; 120(1):229-243. PMC: 5467317. DOI: 10.1161/CIRCRESAHA.116.308537. View

Mehta P, McAuley D, Brown M, Sanchez E, Tattersall R, Manson J . COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395(10229):1033-1034. PMC: 7270045. DOI: 10.1016/S0140-6736(20)30628-0. View

Gorabi A, Kiaie N, Bianconi V, Jamialahmadi T, Al-Rasadi K, Johnston T . Antiviral effects of statins. Prog Lipid Res. 2020; 79:101054. DOI: 10.1016/j.plipres.2020.101054. View

Mahdavi Gorabi A, Kiaie N, Hajighasemi S, Banach M, Penson P, Jamialahmadi T . Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications. J Clin Med. 2019; 8(12). PMC: 6947613. DOI: 10.3390/jcm8122051. View

Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H . Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130(5):2620-2629. PMC: 7190990. DOI: 10.1172/JCI137244. View

Zhang X, Qin J, Cheng X, Shen L, Zhao Y, Yuan Y . In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metab. 2020; 32(2):176-187.e4. PMC: 7311917. DOI: 10.1016/j.cmet.2020.06.015. View

Jagannathan P, Lutwama F, Boyle M, Nankya F, Farrington L, McIntyre T . Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure. Sci Rep. 2017; 7(1):11487. PMC: 5597587. DOI: 10.1038/s41598-017-10624-3. View

10.

Lei L, Qian H, Yang X, Zhang X, Zhang D, Dai T . The phenotypic changes of γδ T cells in COVID-19 patients. J Cell Mol Med. 2020; 24(19):11603-11606. PMC: 7576249. DOI: 10.1111/jcmm.15620. View

11.

Feng Y . Efficacy of statin therapy in patients with acute respiratory distress syndrome/acute lung injury: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2018; 22(10):3190-3198. DOI: 10.26355/eurrev_201805_15080. View

12.

Gober H, Kistowska M, Angman L, Jeno P, Mori L, De Libero G . Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med. 2003; 197(2):163-8. PMC: 2193814. DOI: 10.1084/jem.20021500. View

13.

Castiglione V, Chiriaco M, Emdin M, Taddei S, Vergaro G . Statin therapy in COVID-19 infection. Eur Heart J Cardiovasc Pharmacother. 2020; 6(4):258-259. PMC: 7197622. DOI: 10.1093/ehjcvp/pvaa042. View

14.

Iwata A, Shirai R, Ishii H, Kushima H, Otani S, Hashinaga K . Inhibitory effect of statins on inflammatory cytokine production from human bronchial epithelial cells. Clin Exp Immunol. 2012; 168(2):234-40. PMC: 3390525. DOI: 10.1111/j.1365-2249.2012.04564.x. View

15.

Davoodi L, Jafarpour H, Oladi Z, Zakariaei Z, Tabarestani M, Ahmadi B . Atorvastatin therapy in COVID-19 adult inpatients: A double-blind, randomized controlled trial. Int J Cardiol Heart Vasc. 2021; 36:100875. PMC: 8437805. DOI: 10.1016/j.ijcha.2021.100875. View

16.

Rha M, Shin E . Activation or exhaustion of CD8 T cells in patients with COVID-19. Cell Mol Immunol. 2021; 18(10):2325-2333. PMC: 8374113. DOI: 10.1038/s41423-021-00750-4. View

17.

Dashti-Khavidaki S, Khalili H . Considerations for Statin Therapy in Patients with COVID-19. Pharmacotherapy. 2020; 40(5):484-486. PMC: 7262253. DOI: 10.1002/phar.2397. View

18.

Arora M, Chen L, Paglia M, Gallagher I, Allen J, Vyas Y . Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells. Proc Natl Acad Sci U S A. 2006; 103(20):7777-82. PMC: 1472521. DOI: 10.1073/pnas.0508492103. View

19.

Carissimo G, Xu W, Kwok I, Abdad M, Chan Y, Fong S . Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19. Nat Commun. 2020; 11(1):5243. PMC: 7568554. DOI: 10.1038/s41467-020-19080-6. View

20.

Cerapio J, Perrier M, Pont F, Tosolini M, Laurent C, Bertani S . Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease. Viruses. 2021; 13(11). PMC: 8623150. DOI: 10.3390/v13112212. View