KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2− ILCs biased toward ILC2 or ILC3

Maho Nagasawa,Suzanne M Bal,Itziar Martinez-Gonzalez,Marjolein J.W De Bruijn,Rudi W Hendriks,Hergen Spits,Korneliusz Golebski,Lisette Krabbendam,Balthasar A Heesters,Ralph Stadhouders,Chantal M.A Kradolfer

doi:10.1084/jem.20190490

Maho Nagasawa, Suzanne M Bal + Show 9 more

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https://doi.org/10.1084/jem.20190490

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Abstract

Recently, human ILCs that express CD117 and CD127 but lack CRTH2 and NKp44 have been shown to contain precursors of ILC1, ILC2, and ILC3. However, these ILCs have not been extensively characterized. We performed an unbiased hierarchical stochastic neighbor embedding (HSNE) analysis of the phenotype of peripheral blood CD117+ ILCs, which revealed the presence of three major subsets: the first expressed NKp46, the second expressed both NKp46 and CD56, and the third expressed KLRG1, but not NKp46 or CD56. Analysis of their cytokine production profiles and transcriptome revealed that NKp46+ ILCs predominantly develop into ILC3s; some of them can differentiate into ILC1/NK-like cells, but they are unable to develop into ILC2s. In contrast, KLRG1+ ILCs predominantly differentiate into ILC2s. Single-cell cultures demonstrate that KLRG1+ ILCs can also differentiate into other ILC subsets depending on the signals they receive. Epigenetic profiling of KLRG1+ ILCs is consistent with the broad differentiation potential of these cells.

Highlights

Innate lymphoid cells (ILCs) exert their effector functions most The CD117+CRTH2− population was recently shown to consist prominently in tissues, at mucosal sites
The CD56+CD200R+ ILCs are probably similar to the CD56+ ILCs that were recently described in tonsils to give rise to natural killer (NK) cells, ILC1s, and ILC3s (Chen et al, 2018)
The production of IFN-γ was increased upon culture of both NKp46+ and KLRG1+ ILCs with IL-1β and IL-12 (Fig. 4 E). This was accompanied by down-regulation of CD117 and NKp44 expression, indicating that these cells transdifferentiated into ILC1s in response to IL-12, as we have previously shown for CRTH2+ ILC2s and NKp44+ ILC3s (Fig. 4 F; Bernink et al, 2015; Bal et al, 2016)

Summary

Introduction

Innate lymphoid cells (ILCs) exert their effector functions most The CD117+CRTH2− population was recently shown to consist prominently in tissues, at mucosal sites. ILCs are of uni- and multipotent precursors of mature ILC1, ILC2, ILC3, rapidly activated by various stimuli produced by other immune and NK-like cells (Lim et al, 2017). Consistent with their and nonimmune cells, and this allows for an efficient response to differentiation potential, CD117+CRTH2− ILCs express high the acute phase of infections and tissue damage Moderate to low levels of the developmental trajectory, transcription factor (TF) require- lineage-determining TFs RORC, T-BOX 21 (TBX21), Eomesoments, and cytokine production profiles (Vivier et al, 2018). dermin (EOMES), cytokine receptors, and signature cytokines

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