Endothelial cells express NKG2D ligands and desensitize anti-tumor NK responses

Abstract
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Abstract

Natural Killer (NK) cells confer protection from tumors and infections by releasing cytotoxic granules and pro-inflammatory cytokines upon recognition of diseased cells. The responsiveness of NK cells to acute stimulation is dynamically tuned by steady-state receptor-ligand interactions of an NK cell with its cellular environment. Here we demonstrate that in healthy WT mice the NK activating receptor NKG2D is engaged in vivo by one of its ligands, RAE-1ε, which is expressed constitutively by lymph node endothelial cells and highly induced on tumor-associated endothelium. This interaction causes internalization of NKG2D from the NK cell surface and transmits an NK-intrinsic signal that desensitizes NK cell responses globally to acute stimulation, resulting in impaired NK anti-tumor responses in vivo.

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Thornton W Thompson

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Alexander Byungsuk Kim

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-6425-4566
Po-Yi Jonathan Li

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Jiaxi Wang

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Benjamin T Jackson

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Kristen Ting Hui Huang

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
Lily Zhang

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

Competing interests
No competing interests declared.
David H Raulet

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

For correspondence
raulet@berkeley.edu

Competing interests
David H Raulet, Co-founder of Dragonfly Therapeutics, and serves on the Scientific Advisory Boards of Innate Pharma, Aduro Biotech and Ignite Immmunotherapy, has a financial interest in all four companies and received research support from Innate Pharma, and may benefit from commercialization of the results of this research.

"This ORCID iD identifies the author of this article:" 0000-0002-1257-8649

Funding

National Cancer Institute (R01 CA093678)

David H Raulet

Innate Pharma, SAS

David H Raulet

National Cancer Institute (F31 CA203262)

Thornton W Thompson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All mice were maintained at the University of California, Berkeley and experiments were conducted in accordance with approved protocols from the Animal Care and Use Committee, under protocol number AUP-2015-10-8058.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.