The SIRPα-CD47 immune checkpoint in NK cells

Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and...

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Veröffentlicht in:The Journal of experimental medicine 2021-03, Vol.218 (3)
Hauptverfasser: Deuse, Tobias, Hu, Xiaomeng, Agbor-Enoh, Sean, Jang, Moon K, Alawi, Malik, Saygi, Ceren, Gravina, Alessia, Tediashvili, Grigol, Nguyen, Vinh Q, Liu, Yuan, Valantine, Hannah, Lanier, Lewis L, Schrepfer, Sonja
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container_issue 3
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container_title The Journal of experimental medicine
container_volume 218
creator Deuse, Tobias
Hu, Xiaomeng
Agbor-Enoh, Sean
Jang, Moon K
Alawi, Malik
Saygi, Ceren
Gravina, Alessia
Tediashvili, Grigol
Nguyen, Vinh Q
Liu, Yuan
Valantine, Hannah
Lanier, Lewis L
Schrepfer, Sonja
description Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I-deficient target cells against SIRPα+ primary NK cells, but not against SIRPα- NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα-CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell-mediated killing of allogeneic and xenogeneic tissues.
doi_str_mv 10.1084/jem.20200839
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subjects Animals
CD47 Antigen - metabolism
Cells, Cultured
Cytokines - pharmacology
Cytotoxicity, Immunologic - drug effects
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Histocompatibility Antigens Class I - metabolism
Humans
Immune Checkpoint Inhibitors
Innate immunity and inflammation
Killer Cells, Natural - drug effects
Killer Cells, Natural - metabolism
Macaca mulatta
Macrophages - drug effects
Macrophages - metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Protein Binding - drug effects
Receptors, Immunologic - metabolism
Species Specificity
Stem Cells & Regeneration
title The SIRPα-CD47 immune checkpoint in NK cells
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