The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation

Nat Immunol. 2020 Oct;21(10):1205-1218. doi: 10.1038/s41590-020-0758-6.

Susanna S Ng ¹ ² ³, Fabian De Labastida Rivera ¹, Juming Yan ¹ ⁴, Dillon Corvino ¹ ⁴ ³, Indrajit Das ¹, Ping Zhang ¹, Rachel Kuns ¹, Shashi Bhushan Chauhan ⁵, Jiajie Hou ¹, Xian-Yang Li ¹, Teija C M Frame ¹ ⁴, Benjamin A McEnroe ¹, Eilish Moore ¹ ⁴, Jinrui Na ¹ ⁴, Jessica A Engel ¹, Megan S F Soon ¹ ⁴, Bhawana Singh ⁵, Andrew J Kueh ⁶ ⁷, Marco J Herold ⁶ ⁷, Marcela Montes de Oca ¹, Siddharth Sankar Singh ⁵, Patrick T Bunn ¹ ⁸, Amy Roman Aguilera ¹, Mika Casey ¹, Matthias Braun ¹, Nazanin Ghazanfari ⁹, Shivangi Wani ¹ ¹⁰, Yulin Wang ¹ ², Fiona H Amante ¹, Chelsea L Edwards ¹ ⁴, Ashraful Haque ¹, William C Dougall ¹, Om Prakash Singh ¹¹, Alan G Baxter ¹², Michele W L Teng ¹, Alex Loukas ¹³, Norelle L Daly ¹³, Nicole Cloonan ¹ ¹⁴, Mariapia A Degli-Esposti ¹⁵ ¹⁶, Jude Uzonna ¹⁷, William R Heath ⁹, Tobias Bald ¹, Siok-Keen Tey ¹, Kyohei Nakamura ¹, Geoffrey R Hill ¹⁸, Rajiv Kumar ⁵ ¹⁹, Shyam Sundar ^# ⁵, Mark J Smyth ^# ¹, Christian R Engwerda ^# ²⁰

Affiliations

1 QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
2 School of Environment and Science, Griffith University, Nathan, Queensland, Australia.
3 Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
4 School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
5 Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
6 Division of Blood Cells and Blood Cancer, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
7 Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
8 Institute of Glycomics, Griffith University, Gold Coast, Queensland, Australia.
9 Department of Microbiology and Immunology, The Peter Doherty Institute, University of Melbourne, Melbourne, Victoria, Australia.
10 Institute of Molecular Biology, University of Queensland, Brisbane, Queensland, Australia.
11 Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India.
12 College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, Queensland, Australia.
13 Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia.
14 Faculty of Science, University of Auckland, Auckland, New Zealand.
15 Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
16 The Centre for Experimental Immunology, Lions Eye Institute, Perth, Western Australia, Australia.
17 Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
18 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
19 Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
20 QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. chrisE@qimr.edu.au.
# Contributed equally.

PMID: 32839608 DOI: 10.1038/s41590-020-0758-6

Abstract

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly Cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4⁺ and CD8⁺ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling Cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8⁺ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4⁺ T cell activation following Infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.

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