Clinical Staphylococcus aureus inhibits human T-cell activity through interaction with the PD-1 receptor
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Staphylococcus aureus (S. aureus) represents a major clinical challenge due to its explicit capacity to select mutations that increase antibiotic resistance and immune evasion. However, the molecular mechanisms are poorly defined, especially for adaptive immunity. Cancer immunotherapy targeting programmed cell death protein 1 (PD-1) enhances T-cell activity and is emerging for the treatment of certain viral infections, while its potential against bacterial infections remains elusive. We show that an S. aureus clpP mutant, selected during clinical antibiotic therapy, inhibits T-cell activity by directly interacting with PD-1 on human T cells. Specificity of the interaction was confirmed using recombinant PD-1, as well as PD-1 overexpressing and knock out cells. Moreover, the PD-1-binding S. aureus inhibited intracellular calcium mobilization, T-cell proliferation, CD25 expression, and IL-2 secretion, while the key effects were alleviated by antibody-mediated PD-1 blockade using an engineered IgG1-based anti-PD-1 antibody. Our results suggest that clpP mutant S. aureus directly targets PD-1 to evade immune activation and that therapeutic targeting of PD-1 may be used against certain staphylococcal infections.
Originalsprog | Engelsk |
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Artikelnummer | e01349-23 |
Tidsskrift | mBio |
Vol/bind | 14 |
Udgave nummer | 5 |
Antal sider | 21 |
ISSN | 2161-2129 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Else og Mogens Wedell Wedellsborgs Fond (Else and Mogens Wedell Wedellsborgs Fund) Grant 3A-17-1 Sundhed og Sygdom, Det Frie Forskningsråd (FSS, DFF) DFF-6111-00499 Novo Nordisk Fonden (NNF) NNF15CC0018346 Novo Nordisk Fonden (NNF) NNF20SA0066621, NNF19SA0035474, NNF19SA0056783, NNF21SA0072683 The National Health and Medical Research Council Australia GNT1196103 The National Health and Medical Research Council Australia GNT1194325
Funding Information:
Finally, thanks go to the funders of this work, which was supported by Ph.D. Scholarship A3507 from the University of Copenhagen Faculty of Health and Medical Sciences (to M.M.), Else and Mogens Wedell Wedellsborg Foundation Grant 3 A-17-1 (to M.M.), Danish Council for Independent Research Grant DFF-6111-00499 (to S.S.), Novo Nordisk Foundation Grant NNF15CC0018346 (to S.S.), and Novo Nordisk Foundation Grants NNF20SA0066621, NNF19SA0056783, NNF21SA0072683, and NNF19SA0035474 (to S.G.). The National Health and Medical Research Council Australia supported this work through Investigator Fellowships GNT1196103 (to B.P.H.) and GNT1194325 (to T.P.S.).
Publisher Copyright:
Copyright © 2023 Mellergaard et al.
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