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A temporal developmental map separates human NK cells from noncytotoxic ILCs through clonal and single-cell analysis

Vo, Dang Nghiem LU ; Yuan, Ouyang LU ; Kanaya, Minoru ; Telliam-Dushime, Gladys LU ; Li, Hongzhe LU ; Kotova, Olga LU ; Caglar, Emel LU ; Honnens de Lichtenberg, Kristian ; Rahman, Shamim Herbert and Soneji, Shamit LU , et al. (2024) In Blood Advances 8(11). p.2933-2951
Abstract

Natural killer (NK) cells represent the cytotoxic member within the innate lymphoid cell (ILC) family that are important against viral infections and cancer. Although the NK cell emergence from hematopoietic stem and progenitor cells through multiple intermediate stages and the underlying regulatory gene network has been extensively studied in mice, this process is not well characterized in humans. Here, using a temporal in vitro model to reconstruct the developmental trajectory of NK lineage, we identified an ILC-restricted oligopotent stage 3a CD34-CD117+CD161+CD45RA+CD56- progenitor population, that exclusively gave rise to CD56-expressing ILCs in vitro. We also further investigated a previously nonappreciated heterogeneity within... (More)

Natural killer (NK) cells represent the cytotoxic member within the innate lymphoid cell (ILC) family that are important against viral infections and cancer. Although the NK cell emergence from hematopoietic stem and progenitor cells through multiple intermediate stages and the underlying regulatory gene network has been extensively studied in mice, this process is not well characterized in humans. Here, using a temporal in vitro model to reconstruct the developmental trajectory of NK lineage, we identified an ILC-restricted oligopotent stage 3a CD34-CD117+CD161+CD45RA+CD56- progenitor population, that exclusively gave rise to CD56-expressing ILCs in vitro. We also further investigated a previously nonappreciated heterogeneity within the CD56+CD94-NKp44+ subset, phenotypically equivalent to stage 3b population containing both group-1 ILC and RORγt+ ILC3 cells, that could be further separated based on their differential expression of DNAM-1 and CD161 receptors. We confirmed that DNAM-1hi S3b and CD161hiCD117hi ILC3 populations distinctively differed in their expression of effector molecules, cytokine secretion, and cytotoxic activity. Furthermore, analysis of lineage output using DNA-barcode tracing across these stages supported a close developmental relationship between S3b-NK and S4-NK (CD56+CD94+) cells, whereas distant to the ILC3 subset. Cross-referencing gene signatures of culture-derived NK cells and other noncytotoxic ILCs with publicly available data sets validated that these in vitro stages highly resemble transcriptional profiles of respective in vivo ILC counterparts. Finally, by integrating RNA velocity and gene network analysis through single-cell regulatory network inference and clustering we unravel a network of coordinated and highly dynamic regulons driving the cytotoxic NK cell program, as a guide map for future studies on NK cell regulation.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Killer Cells, Natural/immunology, Single-Cell Analysis/methods, Cell Lineage, Immunity, Innate, Cell Differentiation
in
Blood Advances
volume
8
issue
11
pages
2933 - 2951
publisher
American Society of Hematology
external identifiers
  • pmid:38484189
ISSN
2473-9529
DOI
10.1182/bloodadvances.2023011909
language
English
LU publication?
yes
additional info
© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
id
41673468-aa1f-4511-a7e4-4e43bdab3398
date added to LUP
2024-09-12 15:27:10
date last changed
2024-09-12 16:24:14
@article{41673468-aa1f-4511-a7e4-4e43bdab3398,
  abstract     = {{<p>Natural killer (NK) cells represent the cytotoxic member within the innate lymphoid cell (ILC) family that are important against viral infections and cancer. Although the NK cell emergence from hematopoietic stem and progenitor cells through multiple intermediate stages and the underlying regulatory gene network has been extensively studied in mice, this process is not well characterized in humans. Here, using a temporal in vitro model to reconstruct the developmental trajectory of NK lineage, we identified an ILC-restricted oligopotent stage 3a CD34-CD117+CD161+CD45RA+CD56- progenitor population, that exclusively gave rise to CD56-expressing ILCs in vitro. We also further investigated a previously nonappreciated heterogeneity within the CD56+CD94-NKp44+ subset, phenotypically equivalent to stage 3b population containing both group-1 ILC and RORγt+ ILC3 cells, that could be further separated based on their differential expression of DNAM-1 and CD161 receptors. We confirmed that DNAM-1hi S3b and CD161hiCD117hi ILC3 populations distinctively differed in their expression of effector molecules, cytokine secretion, and cytotoxic activity. Furthermore, analysis of lineage output using DNA-barcode tracing across these stages supported a close developmental relationship between S3b-NK and S4-NK (CD56+CD94+) cells, whereas distant to the ILC3 subset. Cross-referencing gene signatures of culture-derived NK cells and other noncytotoxic ILCs with publicly available data sets validated that these in vitro stages highly resemble transcriptional profiles of respective in vivo ILC counterparts. Finally, by integrating RNA velocity and gene network analysis through single-cell regulatory network inference and clustering we unravel a network of coordinated and highly dynamic regulons driving the cytotoxic NK cell program, as a guide map for future studies on NK cell regulation.</p>}},
  author       = {{Vo, Dang Nghiem and Yuan, Ouyang and Kanaya, Minoru and Telliam-Dushime, Gladys and Li, Hongzhe and Kotova, Olga and Caglar, Emel and Honnens de Lichtenberg, Kristian and Rahman, Shamim Herbert and Soneji, Shamit and Scheding, Stefan and Bryder, David and Malmberg, Karl-Johan and Sitnicka, Ewa}},
  issn         = {{2473-9529}},
  keywords     = {{Humans; Killer Cells, Natural/immunology; Single-Cell Analysis/methods; Cell Lineage; Immunity, Innate; Cell Differentiation}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{11}},
  pages        = {{2933--2951}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood Advances}},
  title        = {{A temporal developmental map separates human NK cells from noncytotoxic ILCs through clonal and single-cell analysis}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2023011909}},
  doi          = {{10.1182/bloodadvances.2023011909}},
  volume       = {{8}},
  year         = {{2024}},
}