Expansions of adaptive-like NK cells with a tissue-resident phenotype in human lung and blood

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Significance

Respiratory diseases are leading causes of death worldwide. However, the local immune cell composition in the human lung and individual outliers within the population still remain largely undescribed. We here identify adaptive-like NK cell expansions with tissue-resident traits in lung and blood in approximately 20% of individuals. This particular NK cell subset, which differed from adaptive-like CD16 ⁺ blood NK cells, was hyperresponsive to target cell stimulation. Individuals with such in vivo-primed, expanded NK cells will likely experience a different course of acute lung disease such as viral infections. Furthermore, we believe that target cell-hyperresponsive tissue-resident NK cells represent a future tool in the treatment of lung cancer.

Abstract

Human adaptive-like “memory” CD56 ^dimCD16 ⁺ natural killer (NK) cells in peripheral blood from cytomegalovirus-seropositive individuals have been extensively investigated in recent years and are currently explored as a treatment strategy for hematological cancers. However, treatment of solid tumors remains limited due to insufficient NK cell tumor infiltration, and it is unknown whether large expansions of adaptive-like NK cells that are equipped for tissue residency and tumor homing exist in peripheral tissues. Here, we show that human lung and blood contains adaptive-like CD56 ^brightCD16 ⁻ NK cells with hallmarks of tissue residency, including expression of CD49a. Expansions of adaptive-like lung tissue-resident NK (trNK) cells were found to be present independently of adaptive-like CD56 ^dimCD16 ⁺ NK cells and to be hyperresponsive toward target cells. Together, our data demonstrate that phenotypically, functionally, and developmentally distinct subsets of adaptive-like NK cells exist in human lung and blood. Given their tissue-related character and hyperresponsiveness, human lung adaptive-like trNK cells might represent a suitable alternative for therapies targeting solid tumors.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 16 March 2021

Publication date (Electronic): 08 March 2021

Publication date PMC-release: 08 March 2021

Volume: 118

Issue: 11

Electronic Location Identifier: e2016580118

Affiliations

[1] ^aCenter for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet , 14152 Stockholm, Sweden;

[2] ^bDepartment of Cell and Molecular Biology, Karolinska Institutet , 171 77 Stockholm, Sweden;

[3] ^cTranslational Immunology Research Program, University of Helsinki , 00014 Helsinki, Finland;

[4] ^dDepartment of Bacteriology and Immunology, University of Helsinki , 00014 Helsinki, Finland;

[5] ^eHelsinki University Central Hospital Laboratory, Division of Clinical Microbiology, Helsinki University Hospital , 00290 Helsinki, Finland;

[6] ^fDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104;

[7] ^gInstitute for Immunology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104;

[8] ^hThoracic Surgery, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet , 171 76 Stockholm, Sweden

Author notes

³To whom correspondence may be addressed. Email: nicole.marquardt@ 123456ki.se .

Edited by Marco Colonna, Washington University in St. Louis School of Medicine, St. Louis, MO, and approved January 27, 2021 (received for review August 18, 2020)

Author contributions: N.M. and J.M. designed research; D.B., M.S., J.E.M., J.H., J.N.W., N.M., and J.M. performed research; M.A.-A. contributed new reagents/analytic tools; D.B., M.S., J.E.M., J.H., E.K., M.B., S.N., J.N.W., N.M., and J.M. analyzed data; H.-G.L., N.M., and J.M. provided funding; and H.-G.L., N.M., and J.M. wrote the paper.

¹D.B. and M.S. contributed equally to this work.

²N.M. and J.M. contributed equally to this work.