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

Jennifer A Walker,Paula A Clark,Alastair Crisp,Jillian L Barlow,Aydan Szeto,Ana C.F Ferreira,Batika M.J Rana,Helen E Jolin,Noe Rodriguez-Rodriguez,Meera Sivasubramaniam,Richard Pannell,James Cruickshank,Maria Daly,Liora Haim-Vilmovsky,Sarah A Teichmann,Andrew N.J Mckenzie

doi:10.1016/j.immuni.2019.05.002

Abstract

SummaryInnate 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.

Highlights

Innate lymphoid cells (ILCs) play roles in homeostasis and responses to injury and infection (Colonna, 2018; Eberl et al, 2015; Vivier et al, 2018)
It has been suggested that ILC1s, ILC2s, and ILC3s are the innate counterparts of CD4+ T cells, whereas natural killer (NK) are the innate manifestation of cytolytic CD8+ T cells
Rorc-Kat was expressed in lymphoid tissue inducer (LTi) cells, NKp46+NK1.1À ILC3s and the majority of NKp46+NK1.1+ ILCs, representing ‘‘ILC1 or ex-ILC3’’ (Figures 1A and 1B)

Summary

Introduction

Innate lymphoid cells (ILCs) play roles in homeostasis and responses to injury and infection (Colonna, 2018; Eberl et al, 2015; Vivier et al, 2018). ILC subtypes can react rapidly in situ to tissue-associated microenvironmental cues, such as those released upon perturbation of mucosal barrier surfaces. The previously defined IFN-g-producing natural killer (NK) cells are closely related to ILC1s but require the TF Eomes for their development, and have profound cytolytic activity (Colonna, 2018; Vivier et al, 2018). ILC1 and NK cells share several surface markers, such as NK1.1 and NKp46. It has been suggested that ILC1s, ILC2s, and ILC3s are the innate counterparts of CD4+ T cells, whereas NKs are the innate manifestation of cytolytic CD8+ T cells

Methods

Results

Discussion

Conclusion