期刊
IMMUNITY INFLAMMATION AND DISEASE
卷 6, 期 1, 页码 34-46出版社
WILEY
DOI: 10.1002/iid3.190
关键词
CD49a antigen; chemokine receptor 6 protein; cytokines; human liver; natural killer cells
类别
资金
- Medical Research Council (MRC)
- National Institute for Health Research (NIHR) Clinical Research Network (NIHR) [17075]
- NIHR Wellcome Trust Southampton Clinical Research Facility
- Medical Research Council [MR/M019829/1, MR/L016567/1, G1001738] Funding Source: researchfish
- MRC [G1001738, MR/M019829/1, MR/L016567/1] Funding Source: UKRI
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 IFN and TNF, 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 IFN 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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