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Immunity. 2019 Jul 16;51(1):104-118.e7. doi: 10.1016/j.immuni.2019.05.002. Epub 2019 May 22.

Polychromic Reporter Mice Reveal Unappreciated Innate Lymphoid Cell Progenitor Heterogeneity and Elusive ILC3 Progenitors in Bone Marrow.

Author information

1
MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom.
2
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA UK.
3
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA UK; Theory of Condensed Matter, Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK.
4
MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, United Kingdom. Electronic address: anm@mrc-lmb.cam.ac.uk.

Abstract

Innate lymphoid cells (ILCs) play strategic roles in tissue homeostasis and immunity. ILCs arise from lymphoid progenitors undergoing lineage restriction and the development of specialized ILC subsets. We generated "5x polychromILC" transcription factor reporter mice to delineate ILC precursor states by revealing the multifaceted expression of key ILC-associated transcription factors (Id2, Bcl11b, Gata3, RORγt, and RORα) during ILC development in the bone marrow. This approach allowed previously unattained enrichment of rare progenitor subsets and revealed hitherto unappreciated ILC precursor heterogeneity. In vivo and in vitro assays identified precursors with potential to generate all ILC subsets and natural killer (NK) cells, and also permitted discrimination of elusive ILC3 bone marrow antecedents. Single-cell gene expression analysis identified a discrete ILC2-committed population and delineated transition states between early progenitors and a highly heterogeneous ILC1, ILC3, and NK precursor cell cluster. This diversity might facilitate greater lineage potential upon progenitor recruitment to peripheral tissues.

KEYWORDS:

ILC development; ILC progenitors; ILC3 progenitor; bone marrow

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