title: CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver.
abstract: 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.
authors.affiliation: Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, UK.
authors.forename: Kerstin A
authors.initials: KA
authors.lastname: Stegmann
authors.affiliation: Department of Surgery and Interventional Science, UCL, Royal Free Hospital London, London, United Kingdom.
authors.forename: Francis
authors.initials: F
authors.lastname: Robertson
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Bart's and the London School of Medicine and Dentistry, London, UK.
authors.forename: Navjyot
authors.initials: N
authors.lastname: Hansi
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Bart's and the London School of Medicine and Dentistry, London, UK.
authors.forename: Upkar
authors.initials: U
authors.lastname: Gill
authors.affiliation: Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, UK.
authors.forename: Celeste
authors.initials: C
authors.lastname: Pallant
authors.affiliation: Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, UK.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Christophides
authors.affiliation: Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Pallett
authors.affiliation: Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, UK.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Peppa
authors.affiliation: Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Dunn
authors.affiliation: Department of Surgery and Interventional Science, UCL, Royal Free Hospital London, London, United Kingdom.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fusai
authors.affiliation: Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Male
authors.affiliation: Department of Surgery and Interventional Science, UCL, Royal Free Hospital London, London, United Kingdom.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Davidson
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Bart's and the London School of Medicine and Dentistry, London, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kennedy
authors.affiliation: Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, London, UK.
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000737:chemistry / Q000145:classification / Q000276:immunology*; D008099:Liver / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000737:chemistry / Q000145:classification / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000075744:Receptors, CXCR6 / Q000032:analysis*; D020825:T-Box Domain Proteins / Q000032:analysis*; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: C106330:CXCR6 protein, human; D016207:Cytokines; C491199:EOMES protein, human; D000075744:Receptors, CXCR6; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor