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

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 relation...

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Published inNature immunology Vol. 20; no. 9; pp. 1150 - 1160
Main Authors Harly, Christelle, Kenney, Devin, Ren, Gang, Lai, Binbin, Raabe, Tobias, Yang, Qi, Cam, Margaret C., Xue, Hai-Hui, Zhao, Keji, Bhandoola, Avinash
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.09.2019
Nature Publishing Group
Subjects
631/250/232
631/250/2502
631/250/2504
Animals
Biomedical and Life Sciences
Biomedicine
Cancer
Cell Differentiation - immunology
Cell lineage
Cell Lineage - immunology
Cells, Cultured
Chromatin
Cytokines
Dendritic cells
Dendritic Cells - cytology
Developmental stages
Gene Expression Regulation - genetics
Granulocytes
Hepatocyte nuclear factor 1
Hepatocyte Nuclear Factor 1-alpha - genetics
Hepatocyte Nuclear Factor 1-alpha - immunology
Heterogeneity
Homeostasis
Immunology
Infectious Diseases
Life Sciences
Lymphocytes
Lymphocytes T
Lymphoid cells
Lymphoid Progenitor Cells - cytology
Medical research
Medicine
Mice
Mice, Inbred C57BL
RNA sequencing
T cells
T-Lymphocytes - cytology
Transcription factors
Transcription, Genetic - genetics
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Summary: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. Bhandoola and colleagues show that the transcription factor TCF-1 restrains the dendritic cell lineage potential in innate lymphoid cell progenitors.
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Author contributions: CH designed research and performed most of the experiments, with DK and GR; CH, BL, MCC and AB analyzed data; CH, MCC, TR and AB made the Figures; CH, TR, QY and HHX designed and generated new mouse models; CH, KZ and AB directed and oversaw experiments; CH and AB wrote the paper. All authors helped design research, and read and commented on the manuscript. This research was supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, and Center for Cancer Research, and by grants from the NIH (AI121080 and AI139874 to HHX), from the Veteran Affairs BLR&D Merit Review Program (BX002903A to HHX), and from the Foundation pour la Recherche Medicale (DEQ20170839118 to CH).
ISSN:1529-2908
1529-2916
1529-2916
DOI:10.1038/s41590-019-0445-7