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Different developmental pathways generate functionally distinct populations of natural killer cells

ABSTRACT: Natural killer (NK) cells function by eliminating virus-infected cells or tumor cells. Here, we identified a NK lineage-biased progenitor population, termed early NK progenitors (ENKP), which developed into NK cells independently of common precursors for ILCs (ILCPs). ENKP-derived NK cells (ENKP_ NK cells) and ILCP-derived NK cells (ILCP_ NK cells) were also transcriptionally different. We devised combinations of surface markers that identified highly enriched ENKP_NK and ILCP_NK cell populations in wild-type mice. Furthermore, Ly49H+ NK cells that responded to mouse cytomegalovirus (MCMV) infection primarily developed from ENKPs whereas ILCP_NK cells were better IFN-g producers upon Salmonella and Herpes Simplex Virus (HSV) infections. Interestingly, human CD56dim and CD56bright NK cells were transcriptionally similar to ENKP_NK cells and ILCP_NK cells, respectively. Our findings establish the existence of two pathways of NK cell development that generate functionally distinct NK cell subsets in mice, and further suggest these pathways may be conserved in humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE266109 | GEO | 2024/05/24

REPOSITORIES: GEO

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Project description:Human Natural Killer (NK) cells comprise two main subsets, CD56bright and CD56dim cells, that differ in function, phenotype and tissue localization. To further dissect the heterogeneity of CD56dim cells, we have performed transcriptome analysis and functional ex vivo characterization of human NK cell subsets according to the expression of markers related to differentiation, migration or competence. Here, we show for the first time that the ability to respond to cytokines or to activating receptors is mutually exclusive in almost all NK cells with the exception of CD56dim CD62L+ cells. Indeed, only these cells combine the ability to produce interferon (IFN)-gamma after cytokines and proliferate in vivo during viral infection with the capacity to kill and produce cytokines upon engagement of activating receptors. Therefore, CD56dim CD62L+ cells represent a unique subset of polyfunctional NK cells. Ex vivo analysis of their function, phenotype, telomere length, frequencies during ageing as well as transfer experiments of NK cell subsets into immunodeficient mice suggest that CD56dim CD62L+ cells represent an intermediate stage of NK cell maturation, which after restimulation can accomplish multiple tasks and further develop into terminally differentiated effectors. Gene expression profiles of FACSAria sorted CD3- CD56bright CD62L+, CD3- CD56dim CD62L+ and CD3- CD56dim CD62L- NK cells from human peripheral blood of three donors were compared using Affymetrix GeneChip Human Genome HG-U133_Plus_2. After total RNA extraction, reverse transcription, cDNA extraction, the biotinylated cRNA was transcribed, fragmented, and 15 Âµg cRNA hybridized in triplicates for each of the three groups to the GeneChip arrays. Group1: CD3- CD56bright CD62L+,.Group2: CD3- CD56dim CD62L+, Group3: CD3- CD56dim CD62L-. Lists of differentially regulated genes were created using High Performance Chip Data Analysis (HPCDA) with Bioretis database (http://www.bioretis-analysis.de). Worldwide data sharing is possible via Bioretis, please ask the authors.

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Different developmental pathways generate functionally distinct populations of natural killer cells

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OmicsDI is part of the ELIXIR infrastructure

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­­Different developmental pathways generate functionally distinct populations of natural killer cells

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OmicsDI is part of the ELIXIR infrastructure

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Different developmental pathways generate functionally distinct populations of natural killer cells