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Nat Immunol. 2019 Jul 29. doi: 10.1038/s41590-019-0445-7. [Epub ahead of print]

The transcription factor TCF-1 enforces commitment to the innate lymphoid cell lineage.

Author information

1
Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
2
CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.
3
LabEx IGO 'Immunotherapy, Graft, Oncology', Nantes, France.
4
Systems Biology Center, National Heart, Lung, and Blood Institute, National Iinstitutes of Health, Bethesda, MD, USA.
5
Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PL, USA.
6
Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
7
Office of Science and Technology Resources, Office of the Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
8
Department of Microbiology, Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
9
Iowa City Veterans Affairs Health Care System, Iowa City, IA, USA.
10
Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. avinash.bhandoola@nih.gov.

Abstract

Innate lymphoid cells (ILCs) play important functions in immunity and tissue homeostasis, but their development is poorly understood. Through the use of single-cell approaches, we examined the transcriptional and functional heterogeneity of ILC progenitors, and studied the precursor-product relationships that link the subsets identified. This analysis identified two successive stages of ILC development within T cell factor 1-positive (TCF-1+) early innate lymphoid progenitors (EILPs), which we named 'specified EILPs' and 'committed EILPs'. Specified EILPs generated dendritic cells, whereas this potential was greatly decreased in committed EILPs. TCF-1 was dispensable for the generation of specified EILPs, but required for the generation of committed EILPs. TCF-1 used a pre-existing regulatory landscape established in upstream lymphoid precursors to bind chromatin in EILPs. Our results provide insight into the mechanisms by which TCF-1 promotes developmental progression of ILC precursors, while constraining their dendritic cell lineage potential and enforcing commitment to ILC fate.

PMID:
31358996
DOI:
10.1038/s41590-019-0445-7

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