A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms, even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared to healthy controls. Plasma levels of IL-1ß, IL-1RA and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1 as well as of PD1 promoter methylation and PD1-targeting miR-15-5p in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.

PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response / C. Loretelli, A. Abdelsalam, F. D'Addio, M. Ben Nasr, E. Assi, V. Usuelli, A. Maestroni, A.J. Seelam, E. Ippolito, S. Di Maggio, L. Loreggian, D. Radovanovic, C. Vanetti, J. Yang, B. El Essawy, A. Rossi, I. Pastore, L. Montefusco, M.E. Lunati, A.M. Bolla, M. Biasin, S. Antinori, P. Santus, A. Riva, G. Zuccotti, M. Galli, S. Rusconi, P. Fiorina. - In: JCI INSIGHT. - ISSN 2379-3708. - (2021). [Epub ahead of print] [10.1172/jci.insight.146701]

PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response

C. Loretelli
Primo
;
A. Abdelsalam
Secondo
;
F. D'Addio;M. Ben Nasr;E. Assi;V. Usuelli;A. Maestroni;A.J. Seelam;E. Ippolito;S. Di Maggio;L. Loreggian;D. Radovanovic;C. Vanetti;L. Montefusco;M.E. Lunati;M. Biasin;S. Antinori;P. Santus;A. Riva;G. Zuccotti;M. Galli;S. Rusconi
Penultimo
;
P. Fiorina
Ultimo
2021

Abstract

A substantial proportion of patients who have recovered from coronavirus disease-2019 (COVID-19) experience COVID-19-related symptoms, even months after hospital discharge. We extensively immunologically characterized patients who recovered from COVID-19. In these patients, T cells were exhausted, with increased PD-1+ T cells, as compared to healthy controls. Plasma levels of IL-1ß, IL-1RA and IL-8, among others, were also increased in patients who recovered from COVID-19. This altered immunophenotype was mirrored by a reduced ex vivo T cell response to both nonspecific and specific stimulation, revealing a dysfunctional status of T cells, including a poor response to SARS-CoV-2 antigens. Altered levels of plasma soluble PD-L1 as well as of PD1 promoter methylation and PD1-targeting miR-15-5p in CD8+ T cells were also observed, suggesting abnormal function of the PD-1/PD-L1 immune checkpoint axis. Notably, ex vivo blockade of PD-1 nearly normalized the aforementioned immunophenotype and restored T cell function, reverting the observed post-COVID-19 immune abnormalities; indeed, we also noted an increased T cell-mediated response to SARS-CoV-2 peptides. Finally, in a neutralization assay, PD-1 blockade did not alter the ability of T cells to neutralize SARS-CoV-2 spike pseudotyped lentivirus infection. Immune checkpoint blockade ameliorates post-COVID-19 immune abnormalities and stimulates an anti-SARS-CoV-2 immune response.
Anergy; COVID-19; Immunology; Immunotherapy;
Settore MED/13 - Endocrinologia
16-nov-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/883752
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