Toxoplasma gondii infection drives conversion of NK cells into ILC1-like cells
- Washington University School of Medicine, United States
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.
Data availability
GEO accession numbers are noted in Materials and Methods. Accession numbers: GSE124313 (RNA-seq, ATAC-seq) and GSE124577 (scRNA-seq).
-
Toxoplasma gondii Infection Promotes NK Cell Conversion into ILC1s and Heterogeneous ILC1 PopulationsNCBI Gene Expression Omnibus, GSE124577.
Article and author information
Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (F30DK108472)
- Eugene Park
National Institute of Allergy and Infectious Diseases (AI128845)
- Wayne M Yokoyama
National Institute of Allergy and Infectious Diseases (AI120606)
- Eugene Oltz
National Institute of Allergy and Infectious Diseases (AI134035)
- Eugene Oltz
National Institute of Allergy and Infectious Diseases (AI134035)
- Marco Colonna
National Institute of Allergy and Infectious Diseases (AI11852)
- Eugene Oltz
National Cancer Institute (CA188286)
- Eugene Oltz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All protocols were approved by the Institutional Animal Care and Uses Committee(Washington University School of Medicine, St. Louis, MO) under animal protocol number 20160002.
Copyright
© 2019, Park et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,780
- views
-
- 565
- downloads
-
- 90
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Toxoplasma gondii infection drives conversion of NK cells into ILC1-like cells
eLife 8:e47605.
https://doi.org/10.7554/eLife.47605
Further reading
-
- Genetics and Genomics
- Immunology and Inflammation
Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients’ ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
-
- Immunology and Inflammation
The adaptive T cell response is accompanied by continuous rewiring of the T cell’s electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report in mice that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency in mice causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.
