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 -