Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69-CD56dimcells.
BACKGROUND
In contrast to the extensive knowledge about human natural killer (NK) cells in peripheral blood, relatively little is known about NK cells in the human lung. Knowledge about the composition, differentiation, and function of human lung NK cells is critical to better understand their role in diseases affecting the lung, including asthma, chronic obstructive pulmonary disease, infections, and cancer.


OBJECTIVE
We sought to analyze and compare the phenotypic and functional characteristics of NK cells in the human lung and peripheral blood at the single-cell level.


METHODS
NK cells in human lung tissue and matched peripheral blood from 132 subjects were analyzed by using 16-color flow cytometry and confocal microscopy.


RESULTS
CD56dimCD16+NK cells made up the vast majority of NK cells in human lungs, had a more differentiated phenotype, and more frequently expressed educating killer cell immunoglobulin-like receptors compared with NK cells in peripheral blood. Despite this, human lung NK cells were hyporesponsive toward target cell stimulation, even after priming with IFN-α. Furthermore, we detected a small subset of NK cells expressing CD69, a marker of tissue residency. These CD69+NK cells in the lung consisted predominantly of immature CD56brightCD16-NK cells and less differentiated CD56dimCD16+NK cells.


CONCLUSIONS
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.
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Nicole
N
Marquardt
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Eliisa
E
Kekäläinen
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Puran
P
Chen
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Egle
E
Kvedaraite
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Jennifer N
JN
Wilson
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Martin A
MA
Ivarsson
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Jenny
J
Mjösberg
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Lena
L
Berglin
Unit for Experimental Asthma and Allergy Research, Centre for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Jesper
J
Säfholm
Unit for Experimental Asthma and Allergy Research, Centre for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Respiratory, Inflammation and Autoimmunity (RIA), Innovative Medicines, Astra Zeneca R&D, Gothenburg, Sweden.
Martijn L
ML
Manson
Unit for Experimental Asthma and Allergy Research, Centre for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Mikael
M
Adner
Thoracic Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Mamdoh
M
Al-Ameri
Thoracic Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Per
P
Bergman
Thoracic Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Ann-Charlotte
AC
Orre
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Mattias
M
Svensson
Unit for Experimental Asthma and Allergy Research, Centre for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Barbro
B
Dahlén
Unit for Experimental Asthma and Allergy Research, Centre for Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Sven-Erik
SE
Dahlén
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Hans-Gustaf
HG
Ljunggren
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address: jakob.michaelsson@ki.se.
Jakob
J
Michaëlsson
D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D019002:CD56 Antigen / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology; D008168:Lung / Q000166:cytology* / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D018613:Microscopy, Confocal; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D037181:Lectins, C-Type; D000099192:CD69 Antigens; C522918:NCAM1 protein, human
CD69; Natural killer cells; differentiation; innate lymphoid cells; killer cell immunoglobulin-like receptor; lung; tissue residency