Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69 − CD56 dim cells

Marquardt, Nicole; Kekäläinen, Eliisa; Chen, Puran; Kvedaraite, Egle; Wilson, Jennifer N.; Ivarsson, Martin A.; Mjösberg, Jenny; Berglin, Lena; Säfholm, Jesper; Manson, Martijn L.; Adner, Mikael; Al‐Ameri, Mamdoh; Bergman, Per; Orre, Ann-Charlotte; Svensson, Mattias; Dahlén, Barbro; Dahlén, Sven-Erik; Ljunggren, Hans‐Gustaf; Michaëlsson, Jakob

doi:10.1016/j.jaci.2016.07.043

Cited by 114 publications

(159 citation statements)

References 39 publications

(46 reference statements)

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“…Of interest, lung function in asthma was inversely correlated with the number of BAL CD56 dim NK cells. Unlike BAL (7), CD56 dim NK cells are the dominant NK cell population in peripheral blood and in some lobectomy specimens from patients with lung cancer (18). CD56 dim NK cells can cause lysis of target cells by releasing cytotoxic mediators, including perforin that forms pores in target cell membranes and granzymes and granulysins that enter target cells through these pores to induce apoptosis (19, 20).…”

Section: Discussionmentioning

confidence: 99%

Natural killer cell–mediated inflammation resolution is disabled in severe asthma

et al. 2017

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Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute–sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4+ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6−CCR4− T helper 1–enriched CD4+ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV1) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A4/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A4–exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.

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Section: Discussionmentioning

confidence: 99%

Natural killer cell–mediated inflammation resolution is disabled in severe asthma

et al. 2017

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“…More recently, trNK cell populations have also been described in human BM, spleen, lung, and liver (Aw Yeang et al, 2017; Cuff et al, 2016; Hudspeth et al, 2016; Lugthart et al, 2016; Lunemann et al, 2013; Marquardt et al, 2015; Marquardt et al, 2017; Stegmann et al, 2016). These various populations of human trNK cells described to date share a number of common features with each other and are overall quite distinct from PB CD56 bright cNK cells (Melsen et al, 2016).…”

Section: Non-conventional Nk Cells In Human Tissues: Specialized Trnkmentioning

confidence: 99%

The Broad Spectrum of Human Natural Killer Cell Diversity

et al. 2017

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SUMMARY Natural killer (NK) cells provide protection against infectious pathogens and cancer. For decades it has been appreciated that two major NK cell subsets (CD56bright and CD56dim) exist in humans and have distinct anatomical localization patterns, phenotypes, and functions in immunity. In light of this traditional NK cell dichotomy, it is now clear that the spectrum of human NK cell diversity is much broader than originally appreciated as a result of variegated surface receptor, intracellular signaling molecule, and transcription factor expression; tissue-specific imprinting; and foreign antigen exposure. The recent discoveries of tissue-resident NK cell developmental intermediates, non-NK innate lymphoid cells, and the capacity for NK cells to adapt and differentiate into long-lived memory cells has added further complexity to this field. Here we review our current understanding of the breadth and generation of human NK cell diversity.

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“…94 Initial mapping of NK cells from healthy human tissues demonstrates that the lung contains several distinct populations based on CD56 and NKp46 expression levels. 96,97 Interestingly, most of these NK cells lack the tissue-resident marker CD69, which might suggest that they are predominantly recirculating rather than resident within the lung. 96,97 Interestingly, most of these NK cells lack the tissue-resident marker CD69, which might suggest that they are predominantly recirculating rather than resident within the lung.…”

Section: Ilc3smentioning

confidence: 99%

Tissue‐resident innate immunity in the lung

2019

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The lung is a unique organ that must protect against inhaled pathogens and toxins, without mounting a disproportionate response against harmless particulate matter and without compromising its vital function. Tissue-resident immune cells within the lung provide local immunity and protection from infection but are also responsible for causing disease when dysregulated. There is a growing appreciation of the importance of tissue-resident memory T cells to lung immunity, but non-recirculating, tissue-resident, innate immune cells also exist. These cells provide the first line of defence against pulmonary infection and are essential for co-ordinating the subsequent adaptive response. In this review, we discuss the main lung-resident innate immune subsets and their functions in common pulmonary diseases, such as influenza, bacterial pneumonia, asthma and inflammatory disorders.

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Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69 − CD56 dim cells

Abstract: Here, we characterize the major NK cell populations in the human lung. Our data suggest a model in which the majority of NK cells in the human lung dynamically move between blood and the lung rather than residing in the lung as bona fide tissue-resident CD69 NK cells.

Cited by 114 publications

References 39 publications

Natural killer cell–mediated inflammation resolution is disabled in severe asthma

Natural killer cell–mediated inflammation resolution is disabled in severe asthma

The Broad Spectrum of Human Natural Killer Cell Diversity

Tissue‐resident innate immunity in the lung

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