Clinical Staphylococcus aureus inhibits human T-cell activity through interaction with the PD-1 receptor
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Clinical Staphylococcus aureus inhibits human T-cell activity through interaction with the PD-1 receptor. / Mellergaard, Maiken; Skovbakke, Sarah Line; Jepsen, Stine Dam; Panagiotopoulou, Nafsika; Hansen, Amalie Bøge Rud; Tian, Weihua; Lund, Astrid; Høgh, Rikke Illum; Møller, Sofie Hedlund; Guérillot, Romain; Hayes, Ashleigh S.; Erikstrup, Lise Tornvig; Andresen, Lars; Peleg, Anton Y.; Larsen, Anders Rhod; Stinear, Timothy P.; Handberg, Aase; Erikstrup, Christian; Howden, Benjamin P.; Goletz, Steffen; Frees, Dorte; Skov, Søren.
In: mBio, Vol. 14, No. 5, e01349-23, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Clinical Staphylococcus aureus inhibits human T-cell activity through interaction with the PD-1 receptor
AU - Mellergaard, Maiken
AU - Skovbakke, Sarah Line
AU - Jepsen, Stine Dam
AU - Panagiotopoulou, Nafsika
AU - Hansen, Amalie Bøge Rud
AU - Tian, Weihua
AU - Lund, Astrid
AU - Høgh, Rikke Illum
AU - Møller, Sofie Hedlund
AU - Guérillot, Romain
AU - Hayes, Ashleigh S.
AU - Erikstrup, Lise Tornvig
AU - Andresen, Lars
AU - Peleg, Anton Y.
AU - Larsen, Anders Rhod
AU - Stinear, Timothy P.
AU - Handberg, Aase
AU - Erikstrup, Christian
AU - Howden, Benjamin P.
AU - Goletz, Steffen
AU - Frees, Dorte
AU - Skov, Søren
N1 - Publisher Copyright: Copyright © 2023 Mellergaard et al.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - adaptive immunity
KW - clinical Staphylococcus aureus
KW - ClpP mutation
KW - immune evasion
KW - T cells
U2 - 10.1128/MBIO.01349-23
DO - 10.1128/MBIO.01349-23
M3 - Journal article
C2 - 37796131
AN - SCOPUS:85176775172
VL - 14
JO - mBio
JF - mBio
SN - 2161-2129
IS - 5
M1 - e01349-23
ER -
ID: 383443871