The NK Cell Granule Protein NKG7 Regulates Cytotoxic Granule Exocytosis and Inflammation

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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References

Netea M, Balkwill F, Chonchol M, Cominelli F, Donath M, Giamarellos-Bourboulis E . A guiding map for inflammation. Nat Immunol. 2017; 18(8):826-831. PMC: 5939996. DOI: 10.1038/ni.3790. View

Trapani J, Smyth M . Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol. 2002; 2(10):735-47. DOI: 10.1038/nri911. View

Crawford A, Angelosanto J, Kao C, Doering T, Odorizzi P, Barnett B . Molecular and transcriptional basis of CD4⁺ T cell dysfunction during chronic infection. Immunity. 2014; 40(2):289-302. PMC: 3990591. DOI: 10.1016/j.immuni.2014.01.005. View

Topalian S, Drake C, Pardoll D . Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015; 27(4):450-61. PMC: 4400238. DOI: 10.1016/j.ccell.2015.03.001. View

Wherry E, Ha S, Kaech S, Nicholas Haining W, Sarkar S, Kalia V . Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007; 27(4):670-84. DOI: 10.1016/j.immuni.2007.09.006. View

Schett G, Neurath M . Resolution of chronic inflammatory disease: universal and tissue-specific concepts. Nat Commun. 2018; 9(1):3261. PMC: 6093916. DOI: 10.1038/s41467-018-05800-6. View

Tubo N, Jenkins M . CD4+ T Cells: guardians of the phagosome. Clin Microbiol Rev. 2014; 27(2):200-13. PMC: 3993097. DOI: 10.1128/CMR.00097-13. View

Engwerda C, Ato M, Kaye P . Macrophages, pathology and parasite persistence in experimental visceral leishmaniasis. Trends Parasitol. 2004; 20(11):524-30. DOI: 10.1016/j.pt.2004.08.009. View

Miller L, Baruch D, Marsh K, Doumbo O . The pathogenic basis of malaria. Nature. 2002; 415(6872):673-9. DOI: 10.1038/415673a. View

10.

Montes de Oca M, Kumar R, De Labastida Rivera F, Amante F, Sheel M, Faleiro R . Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology. PLoS Pathog. 2016; 12(1):e1005398. PMC: 4713066. DOI: 10.1371/journal.ppat.1005398. View

11.

Bald T, Landsberg J, Lopez-Ramos D, Renn M, Glodde N, Jansen P . Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation. Cancer Discov. 2014; 4(6):674-87. DOI: 10.1158/2159-8290.CD-13-0458. View

12.

Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman D . IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017; 127(8):2930-2940. PMC: 5531419. DOI: 10.1172/JCI91190. View

13.

Fairfax B, Taylor C, Watson R, Nassiri I, Danielli S, Fang H . Peripheral CD8 T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma. Nat Med. 2020; 26(2):193-199. PMC: 7611047. DOI: 10.1038/s41591-019-0734-6. View

14.

Ribas A, Wolchok J . Cancer immunotherapy using checkpoint blockade. Science. 2018; 359(6382):1350-1355. PMC: 7391259. DOI: 10.1126/science.aar4060. View

15.

Turman M, Yabe T, McSherry C, Bach F, Houchins J . Characterization of a novel gene (NKG7) on human chromosome 19 that is expressed in natural killer cells and T cells. Hum Immunol. 1993; 36(1):34-40. DOI: 10.1016/0198-8859(93)90006-m. View

16.

Aschenbrenner D, Foglierini M, Jarrossay D, Hu D, Weiner H, Kuchroo V . An immunoregulatory and tissue-residency program modulated by c-MAF in human T17 cells. Nat Immunol. 2018; 19(10):1126-1136. PMC: 6402560. DOI: 10.1038/s41590-018-0200-5. View

17.

Engwerda C, Kaye P . Organ-specific immune responses associated with infectious disease. Immunol Today. 2000; 21(2):73-8. DOI: 10.1016/s0167-5699(99)01549-2. View

18.

Engwerda C, Ng S, Bunn P . The Regulation of CD4(+) T Cell Responses during Protozoan Infections. Front Immunol. 2014; 5:498. PMC: 4195384. DOI: 10.3389/fimmu.2014.00498. View

19.

Jenner R, Townsend M, Jackson I, Sun K, Bouwman R, Young R . The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proc Natl Acad Sci U S A. 2009; 106(42):17876-81. PMC: 2764903. DOI: 10.1073/pnas.0909357106. View

20.

Muzumdar M, Tasic B, Miyamichi K, Li L, Luo L . A global double-fluorescent Cre reporter mouse. Genesis. 2007; 45(9):593-605. DOI: 10.1002/dvg.20335. View