Toxoplasma gondii  infection drives conversion of NK cells into ILC1-like cells

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Abstract

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here, we describe Toxoplasma gondii infection converts NK cells into ILC1-like cells that are distinct from both steady-state NK cells and ILC1s in uninfected mice. These cells were Eomes-dependent, indicating that NK cells can give rise to Eomes ^– Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.

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Most cited references 35

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Maturation of mouse NK cells is a 4-stage developmental program.

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Surface density of CD27 and CD11b subdivides mouse natural killer (NK) cells into 4 subsets: CD11b(low)CD27(low), CD11b(low)CD27(high), CD11b(high)CD27(high), and CD11b(high)CD27(low). To determine the developmental relationship between these 4 subsets, we used several complementary approaches. First, we took advantage of NDE transgenic mice that express enhanced green fluorescent protein (EGFP) and diphtheria toxin receptor specifically in NK cells. Diphtheria toxin injection leads to a transient depletion of NK cells, allowing the monitoring of the phenotype of developing EGFP+ NK cells after diphtheria toxin injection. Second, we evaluated the overall proximity between NK-cell subsets based on their global gene profile. Third, we compared the proliferative capacity of NK-cell subsets at steady state or during replenishment of the NK-cell pool. Fourth, we performed adoptive transfers of EGFP+ NK cell subsets from NDE mice into unirradiated mice and followed the fate of transferred cells. The results of these various experiments collectively support a 4-stage model of NK-cell maturation CD11b(low)CD27(low) --> CD11b(low)CD27(high) --> CD11b(high)CD27(high) --> CD11b(high)CD27(low). This developmental program appears to be associated with a progressive acquisition of NK-cell effector functions.

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The diversity of innate lymphoid cells (ILCs) is rapidly expanding. Three ILC classes have emerged, ILC1, ILC2, and ILC3, with ILC1 and ILC3 including several subsets. The classification of some subsets is unclear and it remains controversial whether NK cells and ILC1 are distinct cell types. To address these issues, we analyzed ILCs and NK cells gene expression within mouse small intestine, spleen, and liver, as part of the Immunological Genome Project. Results identify unique gene-expression patterns for some ILCs and overlapping patterns between ILC1 and NK cells, whereas few ILC subsets remain indistinguishable. A transcriptional program shared by small intestine ILCs and a core ILC signature is identified. Transcripts that suggest novel ILC functions and developmental paths are revealed and discussed.

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Natural killer (NK) cells are lymphocytes that play an important role in the immune response to infection and malignancy. Recent studies in mice have shown that stimulation of NK cells with cytokines or in the context of a viral infection results in memory-like properties. We hypothesized that human NK cells exhibit such memory-like properties with an enhanced recall response after cytokine preactivation. In the present study, we show that human NK cells preactivated briefly with cytokine combinations including IL-12, IL-15, and IL-18 followed by a 7- to 21-day rest have enhanced IFN-γ production after restimulation with IL-12 + IL-15, IL-12 + IL-18, or K562 leukemia cells. This memory-like phenotype was retained in proliferating NK cells. In CD56(dim) NK cells, the memory-like IFN-γ response was correlated with the expression of CD94, NKG2A, NKG2C, and CD69 and a lack of CD57 and KIR. Therefore, human NK cells have functional memory-like properties after cytokine activation, which provides a novel rationale for integrating preactivation with combinations of IL-12, IL-15, and IL-18 into NK cell immunotherapy strategies.

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Author and article information

Contributors

Wayne M Yokoyama:

ORCID: https://orcid.org/0000-0002-0566-7264

Alan Sher: Role: Reviewing Editor

Tadatsugu Taniguchi: Role: Senior Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 08 August 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: e47605

Affiliations

[1 ]deptDivision of Rheumatology, Department of Medicine Washington University School of Medicine St. LouisUnited States

[2 ]deptDepartment of Molecular Microbiology Washington University School of Medicine St. LouisUnited States

[3 ]deptDepartment of Pathology and Immunology Washington University School of Medicine St. LouisUnited States

[4 ]deptComputer Technologies Department ITMO University Saint PetersburgRussia

[5 ]deptDepartment of Microbial Infection and Immunity Ohio State University Wexner School of Medicine ColumbusUnited States

NIH, NIAID United States

Institute of Industrial Science, The University of Tokyo Japan

NIH, NIAID United States

The University of Pennsylvania

National Institute of Allergy and Infectious Diseases, National Institutes of Health United States

National Institute of Allergy and Infectious Diseases United States

Author information

Eugene Park http://orcid.org/0000-0002-2617-7571

Marco Colonna http://orcid.org/0000-0001-5222-4987

Wayne M Yokoyama https://orcid.org/0000-0002-0566-7264

Article

Publisher ID: 47605

DOI: 10.7554/eLife.47605

PMC ID: 6703900

PubMed ID: 31393266

SO-VID: 01d29e23-7027-46c7-a32e-3f6647b0f3c5

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 11 April 2019

Date accepted : 08 August 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;

Award ID: F30DK108472

Award Recipient : Eugene Park

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: AI120606

Award Recipient : Eugene Oltz

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: AI134035

Award Recipient : Marco Colonna Eugene Oltz

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: AI11852

Award Recipient : Eugene Oltz

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: CA188286

Award Recipient : Eugene Oltz

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: AI128845

Award Recipient : Wayne M Yokoyama

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Custom metadata

Author impact statement Toxoplasma gondii infection leads to conversion of natural killer cells into cells resembling innate lymphoid cells, group 1, that circulate widely, disrupting current notions suggesting that these cells have distinct lineages.

ScienceOpen disciplines: Life sciences

Keywords: nk cells,ilc,toxoplasma,mouse

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: nk cells, ilc, toxoplasma, mouse