Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep26157
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Funding
- Wellcome Trust Investigator Award
- MRC Career Development Award
- MRC Clinical Research Training Fellowship
- Wellcome Trust Henry Dale Fellowship
- Medical Research Council [MR/M020126/1, G0902009, MR/M008614/1] Funding Source: researchfish
- National Institute for Health Research [10/4001/11] Funding Source: researchfish
- Wellcome Trust [101849/Z/13/Z] Funding Source: researchfish
- MRC [MR/M008614/1, MR/M020126/1, G0902009] Funding Source: UKRI
- Wellcome Trust [101849/Z/13/Z] Funding Source: Wellcome Trust
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Natural killer cells (NK) are highly enriched in the human liver, where they can regulate immunity and immunopathology. We probed them for a liver-resident subset, distinct from conventional bone-marrow-derived NK. CXCR6+ NK were strikingly enriched in healthy and diseased liver compared to blood (p < 0.0001). Human hepatic CXCR6+ NK had an immature phenotype (predominantly CD56(bright)CD16-CD57-), and expressed the tissue-residency marker CD69. CXCR6+ NK produced fewer cytotoxic mediators and pro-inflammatory cytokines than the non-liver-specific CXCR6-fraction. Instead CXCR6+ NK could upregulate TRAIL, a key death ligand in hepatitis pathogenesis. CXCR6 demarcated liver NK into two transcriptionally distinct populations: T-bet(hi)Eomes(lo)(CXCR6-) and T-bet(lo)Eomes(hi)(CXCR6+); the latter was virtually absent in the periphery. The small circulating CXCR6+ subset was predominantly T-bet(hi)Eomes(lo), suggesting its lineage was closer to CXCR6-peripheral than CXCR6+ liver NK. These data reveal a large subset of human liver-resident T-bet(lo)Eomes(hi) NK, distinguished by their surface expression of CXCR6, adapted for hepatic tolerance and inducible antiviral immunity.
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