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IL-12 and IL-15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

IL-12 and IL-15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells
IL-12 and IL-15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

Introduction: murine hepatic NK cells exhibit adaptive features, with liver-specific adhesion molecules CXCR6 and CD49a acting as surface markers.

Methods: we investigated human liver-resident CXCR6+ and CD49a+ NK cells using RNA sequencing, flow cytometry, and functional analysis. We further assessed the role of cytokines in generating NK cells with these phenotypes from the peripheral blood.

Results: hepatic CD49a+ NK cells could be induced using cytokines and produce high quantities of IFNγ and TNFα, in contrast to hepatic CXCR6+ NK cells. RNA sequencing of liver-resident CXCR6+ NK cells confirmed a tolerant immature phenotype with reduced expression of markers associated with maturity and cytotoxicity. Liver-resident double-positive CXCR6 + CD49a+ hepatic NK cells are immature but maintain high expression of Th1 cytokines as observed for single-positive CD49a+ NK cells. We show that stimulation with activating cytokines can readily induce upregulation of both CD49a and CXCR6 on NK cells in the peripheral blood. In particular, IL-12 and IL-15 can generate CXCR6 + CD49a+ NK cells in vitro from NK cells isolated from the peripheral blood, with comparable phenotypic and functional features to liver-resident CD49a+ NK cells, including enhanced IFNγ and NKG2C expression.

Conclusion: IL-12 and IL-15 may be key for generating NK cells with a tissue-homing phenotype and strong Th1 cytokine profile in the blood, and links peripheral activation of NK cells with tissue-homing. These findings may have important therapeutic implications for immunotherapy of chronic liver disease.

Chronic Disease, Female, Gene Expression Regulation/immunology, Humans, Immune Tolerance, Integrin alpha1/immunology, Interleukin-12/immunology, Interleukin-15/immunology, Killer Cells, Natural/immunology, Liver/immunology, Liver Diseases/immunology, Male, Receptors, CXCR6/immunology, Th1 Cells/immunology
2050-4527
34-46
Hydes, Theresa
d842d1ec-c64a-4934-a5a2-7316fea65767
Noll, Angela
f37365aa-043d-40c7-accf-93c2b5bb1511
Salinas-Riester, Gabriela
77d2eb38-bf0b-466b-b89d-7e82c6dbed72
Abuhilal, Mohammed
0f518131-9660-42b1-9937-c27c0a7d631b
Armstrong, Thomas
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Hamady, Zaed
545a1c81-276e-4341-a420-aa10aa5d8ca8
Primrose, John
d85f3b28-24c6-475f-955b-ec457a3f9185
Takhar, Arjun
e2f77012-0993-42e6-af95-597a73b6ce45
Walter, Lutz
52e3f4b9-0482-49f5-a6a5-f9cd0e3e558d
Khakoo, Salim I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273
Hydes, Theresa
d842d1ec-c64a-4934-a5a2-7316fea65767
Noll, Angela
f37365aa-043d-40c7-accf-93c2b5bb1511
Salinas-Riester, Gabriela
77d2eb38-bf0b-466b-b89d-7e82c6dbed72
Abuhilal, Mohammed
0f518131-9660-42b1-9937-c27c0a7d631b
Armstrong, Thomas
3b87df01-cd08-4048-91c4-7390c73a5960
Hamady, Zaed
545a1c81-276e-4341-a420-aa10aa5d8ca8
Primrose, John
d85f3b28-24c6-475f-955b-ec457a3f9185
Takhar, Arjun
e2f77012-0993-42e6-af95-597a73b6ce45
Walter, Lutz
52e3f4b9-0482-49f5-a6a5-f9cd0e3e558d
Khakoo, Salim I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273

Hydes, Theresa, Noll, Angela, Salinas-Riester, Gabriela, Abuhilal, Mohammed, Armstrong, Thomas, Hamady, Zaed, Primrose, John, Takhar, Arjun, Walter, Lutz and Khakoo, Salim I. (2017) IL-12 and IL-15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells. Immunity, Inflammation and Disease, 6 (1), 34-46. (doi:10.1002/iid3.190).

Record type: Article

Abstract

Introduction: murine hepatic NK cells exhibit adaptive features, with liver-specific adhesion molecules CXCR6 and CD49a acting as surface markers.

Methods: we investigated human liver-resident CXCR6+ and CD49a+ NK cells using RNA sequencing, flow cytometry, and functional analysis. We further assessed the role of cytokines in generating NK cells with these phenotypes from the peripheral blood.

Results: hepatic CD49a+ NK cells could be induced using cytokines and produce high quantities of IFNγ and TNFα, in contrast to hepatic CXCR6+ NK cells. RNA sequencing of liver-resident CXCR6+ NK cells confirmed a tolerant immature phenotype with reduced expression of markers associated with maturity and cytotoxicity. Liver-resident double-positive CXCR6 + CD49a+ hepatic NK cells are immature but maintain high expression of Th1 cytokines as observed for single-positive CD49a+ NK cells. We show that stimulation with activating cytokines can readily induce upregulation of both CD49a and CXCR6 on NK cells in the peripheral blood. In particular, IL-12 and IL-15 can generate CXCR6 + CD49a+ NK cells in vitro from NK cells isolated from the peripheral blood, with comparable phenotypic and functional features to liver-resident CD49a+ NK cells, including enhanced IFNγ and NKG2C expression.

Conclusion: IL-12 and IL-15 may be key for generating NK cells with a tissue-homing phenotype and strong Th1 cytokine profile in the blood, and links peripheral activation of NK cells with tissue-homing. These findings may have important therapeutic implications for immunotherapy of chronic liver disease.

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Hydes et al 2017 - Accepted Manuscript
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Hydes et al 2018 Immunity, Inflammation and Disease - Version of Record
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More information

Accepted/In Press date: 11 July 2017
e-pub ahead of print date: 27 September 2017
Published date: 27 September 2017
Keywords: Chronic Disease, Female, Gene Expression Regulation/immunology, Humans, Immune Tolerance, Integrin alpha1/immunology, Interleukin-12/immunology, Interleukin-15/immunology, Killer Cells, Natural/immunology, Liver/immunology, Liver Diseases/immunology, Male, Receptors, CXCR6/immunology, Th1 Cells/immunology

Identifiers

Local EPrints ID: 414602
URI: http://eprints.soton.ac.uk/id/eprint/414602
ISSN: 2050-4527
PURE UUID: 28d8e121-2c98-4c21-a202-aa4dfb7cd1e5
ORCID for Zaed Hamady: ORCID iD orcid.org/0000-0002-4591-5226
ORCID for John Primrose: ORCID iD orcid.org/0000-0002-2069-7605
ORCID for Salim I. Khakoo: ORCID iD orcid.org/0000-0002-4057-9091

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Date deposited: 04 Oct 2017 16:30
Last modified: 16 Mar 2024 05:43

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Contributors

Author: Theresa Hydes
Author: Angela Noll
Author: Gabriela Salinas-Riester
Author: Mohammed Abuhilal
Author: Thomas Armstrong
Author: Zaed Hamady ORCID iD
Author: John Primrose ORCID iD
Author: Arjun Takhar
Author: Lutz Walter
Author: Salim I. Khakoo ORCID iD

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