CXCR6 marks a novel subset of T-betloEomeshi natural killer cells residing in human liver
Open accessAbstract
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 anti-viral immunity.
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The tissue-resident phenotype is represented among CD56 bright cells which constitutively express chemokine receptors CCR5, CXCR6 and the tissue residency marker CD69.
“The tissue-resident phenotype is represented among the CD56 bright cells which constitutively express the chemokine receptors C-C chemokine receptor (CCR)5, CXCR6 and the tissue residency marker CD69(71).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [71]
In Results and Discussion, the paper reports that CXCR6-positive human liver NK cells are predominantly CD56bright and that 95% co-express CD69 directly ex vivo, consistent with a tissue-resident phenotype. It does not report CCR5 expression in this subset or establish that all three markers are constitutively expressed. (LLM, conf=0.88)
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The Role of TRAIL/DRs in the Modulation of Immune Cells and Responses
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The liver as a central "hub" of the immune system: pathophysiological implications
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Liver sampling: a vital window into HBV pathogenesis on the path to functional cure
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A discrete subset of epigenetically primed human NK cells mediates antigen-specific immune responses
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IL‐12 and IL‐15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells
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The human liver microenvironment shapes the homing and function of CD4 + T-cell populations
Wiggins, B. G., Pallett, L. J., Li, X., Davies, S. P., Amin, O. E., Gill, U. S., Kucykowicz, S., Patel, A. M., Aliazis, K., Liu, Y. S., et al. (2021) · Gut · doi:10.1136/gutjnl-2020-323771 · Cited by 55 · see citing works
Self-citationThe Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy
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Eomesodermin and T-bet mark developmentally distinct human natural killer cells
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Natural Killer Cell Integrins and Their Functions in Tissue Residency
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The liver as an immunological barrier redefined by single‐cell analysis
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Liver-Resident NK Cells: The Human Factor
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Roles of Hepatic Innate and Innate-Like Lymphocytes in Nonalcoholic Steatohepatitis
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Modulation of the chemokine/chemokine receptor axis as a novel approach for glioma therapy
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Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy
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NK Cells and Other Cytotoxic Innate Lymphocytes in Colorectal Cancer Progression and Metastasis
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The role of natural killer cells in liver inflammation
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T Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System
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Self-citationHobit expression by a subset of human liver-resident CD56bright Natural Killer cells
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Bone Marrow NK Cells: Origin, Distinctive Features, and Requirements for Tissue Localization
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NK cells limit therapeutic vaccine–induced CD8 + T cell immunity in a PD-L1–dependent manner
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Self-citationSingle-cell RNA sequencing identifies a population of human liver-type ILC1s
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The unique role of innate lymphoid cells in cancer and the hepatic microenvironment
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Liver Fibrosis—From Mechanisms of Injury to Modulation of Disease
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More Than Just a Removal Service: Scavenger Receptors in Leukocyte Trafficking
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Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells
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Intratumor Regulatory Noncytotoxic NK Cells in Patients with Hepatocellular Carcinoma
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Peripheral Tissue Chemokines: Homeostatic Control of Immune Surveillance T Cells
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Natural Killer Cells in Hepatic Ischemia-Reperfusion Injury
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Tissue-resident NK cells and other innate lymphoid cells
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Tissue-Dependent Adaptations and Functions of Innate Lymphoid Cells
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- Authors
- Stegmann, K. A., Robertson, F., Hansi, N., Gill, U., Pallant, C., Christophides, T., Pallett, L. J., Peppa, D., Dunn, C., Fusai, G., Male, V., Davidson, B. R., Kennedy, P., & Maini, M. K.
- Affiliations
- University College London (GB)
- The Royal Free Hospital (GB)
- Queen Mary University of London (GB)
- Corresponding author
- Maini, Mala K.
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-05-23
- Volume
- 6
- Issue
- 1
- Pages
- 26157-26157
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4876507
- OpenAlex
- W2408392972
- Cited by
- 235
- References
- 30
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 12 · 2023: 14 · 2022: 31 · 2021: 21 · 2020: 30 · 2019: 35 · 2018: 29 · 2017: 28 · 2016: 9
- FWCI
- 20.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (101849/Z/13/Z)
- National Institute for Health and Care Research (HTD 556, 10/4001/11)
- Medical Research Council (MR/M008614/1, MR/M020126/1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- CXCR6, natural killer cells, T-bet, Eomes, CD69, TRAIL, hepatitis, NK cell differentiation, antiviral immunity, CD56bright NK cells, tissue-resident NK cells
- MeSH terms
- Receptors, CXCR6, T-bet Transcription Factor, Adolescent, Adult, Aged, Female, Humans, Killer Cells, Natural, Liver, Male, Middle Aged, Immunophenotyping, Lymphocyte Subsets, Cytokines, T-Box Domain Proteins, Young Adult
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