Critical role for the chemokine receptor CXCR6 in NK cell–mediated antigen-specific memory of haptens and viruses

Paust, Silke; Gill, Harvinder Singh; Wang, Bao‐Zhong; Flynn, Michael P.; Moseman, E. Ashley; Senman, Balimkiz; Szczepanik, Marian; Telenti, Amalio; Askenase, Philip W.; Compans, Richard W.; Andrian, Ulrich H. von

doi:10.1038/ni.1953

Cited by 618 publications

(727 citation statements)

References 46 publications

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“…The chemokine receptor (CXCR), CXCR6 12, and adhesion molecule CD49a 13 have been identified as surface markers of memory NK cells in mice. Interestingly these features were generally limited to liver‐resident NK cells.…”

Section: Introductionmentioning

confidence: 99%

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

Hydes

Noll

Salinas-Riester³

et al. 2017

Immunity Inflam & Disease

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IntroductionMurine hepatic NK cells exhibit adaptive features, with liver‐specific adhesion molecules CXCR6 and CD49a acting as surface markers.MethodsWe 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.ResultsHepatic 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.ConclusionIL‐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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Section: Introductionmentioning

confidence: 99%

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

Hydes

Noll

Salinas-Riester³

et al. 2017

Immunity Inflam & Disease

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“…Accumulation of NK cells was also found at the site of inflammation (O'Leary et al 2006). Adoptive transfer experiments revealed that hepatic NK cells, but not splenic NK cells, are capable of mounting a contact hypersensitivity response to haptens (Paust et al 2010). These hepatic cells were found to be mature, CD11b + CD27 − and Ly49C/I + NK cells that had also acquired the Thy-1 marker after activation with the sensitizing hapten.…”

Section: Hepatic Nk Cells Acquire Memory To Haptens and Viruslike Parmentioning

confidence: 98%

“…Surprisingly, von Adrian's work showed that Rag-deficient mice, which are devoid of T and B cells, exhibit robust contact hypersensitivity in response to hapten challenge. This response was mediated by NK cells, which were shown to be both necessary and sufficient (Paust et al 2010). NK cells mediating contact hypersensitivity could be generated from SCID mice, but not from SCID-beige mice, whose NK cells are defective in lytic granule formation (Majewska-Szczepanik et al 2013).…”

Section: Hepatic Nk Cells Acquire Memory To Haptens and Viruslike Parmentioning

confidence: 99%

“…These hepatic cells were found to be mature, CD11b + CD27 − and Ly49C/I + NK cells that had also acquired the Thy-1 marker after activation with the sensitizing hapten. Additional characterization of this subset revealed expression of the chemokine receptor CXCR6, on which they are dependent for function (Paust et al 2010). CXCR6 recognizes the liver-expressed chemokine CXCL16; this receptor-ligand pair has been implicated in cancer metastases (Deng et al 2010) and in iNKT cell survival in mice (Geissmann et al 2005).…”

Section: Hepatic Nk Cells Acquire Memory To Haptens and Viruslike Parmentioning

confidence: 99%

“…CXCR6 recognizes the liver-expressed chemokine CXCL16; this receptor-ligand pair has been implicated in cancer metastases (Deng et al 2010) and in iNKT cell survival in mice (Geissmann et al 2005). Blocking experiments using either anti-CXCR6 or anti-CXCL16 antibodies in mice, and studies using CXCR6-deficient mice, abolished the hapten recall response by these NK cells (Paust et al 2010). CXCR6 + hepatic NK cells from hapten-sensitized mice were also shown to mediate cytotoxicity against hapten-modified B cells in vitro.…”

Section: Hepatic Nk Cells Acquire Memory To Haptens and Viruslike Parmentioning

confidence: 99%

See 2 more Smart Citations

Sweet Is the Memory of Past Troubles: NK Cells Remember

Hendricks

Min‐Oo

Lanier

2015

Natural Killer Cells

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Natural killer (NK) cells are important in host defense against tumors and microbial pathogens. Recent studies indicate that NK cells share many features with the adaptive immune system, and like B cells and T cells, NK cells can acquire immunological memory. Here, we review evidence for NK cell memory and the molecules involved in the generation and maintenance of these self-renewing NK cells that provide enhanced protection of the host.

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Gene Expression Profiling in Pediatric Appendicitis

Dhillon,

Kortbeek,

Baghela

et al. 2024

JAMA Pediatr

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ImportanceAppendicitis is the most common indication for urgent surgery in the pediatric population, presenting across a range of severity and with variable complications. Differentiating simple appendicitis (SA) and perforated appendicitis (PA) on presentation may help direct further diagnostic workup and appropriate therapy selection, including antibiotic choice and timing of surgery.ObjectiveTo provide a mechanistic understanding of the differences in disease severity of appendicitis with the objective of developing improved diagnostics and treatments, specifically for the pediatric population.Design, Setting, and ParticipantsThe Gene Expression Profiling of Pediatric Appendicitis (GEPPA) study was a single-center prospective exploratory diagnostic study with transcriptomic profiling of peripheral blood collected from a cohort of children aged 5 to 17 years with abdominal pain and suspected appendicitis between November 2016 and April 2017 at the Alberta Children’s Hospital in Calgary, Alberta, Canada, with data analysis reported in August 2023. There was no patient follow-up in this study.ExposureSA, PA, or nonappendicitis abdominal pain.Main Outcomes and MeasuresBlood transcriptomics was used to develop a hypothesis of underlying mechanistic differences between SA and PA to build mechanistic hypotheses and blood-based diagnostics.ResultsSeventy-one children (mean [SD] age, 11.8 [3.0] years; 48 [67.6%] male) presenting to the emergency department with abdominal pain and suspected appendicitis were investigated using whole-blood transcriptomics. A central role for immune system pathways was revealed in PA, including a dampening of major innate interferon responses. Gene expression changes in patients with PA were consistent with downregulation of immune response and inflammation pathways and shared similarities with gene expression signatures derived from patients with sepsis, including the most severe sepsis endotypes. Despite the challenges in identifying early biomarkers of severe appendicitis, a 4-gene signature that was predictive of PA compared to SA, with an accuracy of 85.7% (95% CI, 72.8-94.1) was identified.ConclusionsThis study found that PA was complicated by a dysregulated immune response. This finding should inform improved diagnostics of severity, early management strategies, and prevention of further postsurgical complications.

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Critical role for the chemokine receptor CXCR6 in NK cell–mediated antigen-specific memory of haptens and viruses

Cited by 618 publications

References 46 publications

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

Sweet Is the Memory of Past Troubles: NK Cells Remember

Gene Expression Profiling in Pediatric Appendicitis

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