Umbilical cord blood-derived ILC1-like cells constitute a novel precursor for mature KIR+NKG2A- NK cells.

Sabrina Bianca Bennstein,Angela Noll,Sandra Weinhold,Markus Uhrberg,Nadine Scherenschlich,Gesine Kögler,Lutz Walter,Katharina Raba,Angela Riccarda Manser

doi:10.7554/elife.55232

Sabrina Bianca Bennstein, Angela Noll + Show 7 more

Open Access

https://doi.org/10.7554/elife.55232

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Abstract

Despite their identification several years ago, molecular identity and developmental relation between human ILC1 and NK cells, comprising group 1 ILCs, is still elusive. To unravel their connection, thorough transcriptional, epigenetic, and functional characterization was performed from umbilical cord blood (CB). Unexpectedly, ILC1-like cells lacked Tbet expression and failed to produce IFNγ. Moreover, in contrast to previously described ILC1 subsets they could be efficiently differentiated into NK cells. These were characterized by highly diversified KIR repertoires including late stage NKG2A-KIR+ effector cells that are commonly not generated from previously known NK cell progenitor sources. This property was dependent on stroma cell-derived Notch ligands. The frequency of the novel ILC1-like NK cell progenitor (NKP) significantly declined in CB from early to late gestational age. The study supports a model in which circulating fetal ILC1-like NKPs travel to secondary lymphoid tissues to initiate the formation of diversified NK cell repertoires after birth.

Highlights

Innate lymphoid cells (ILC) constitute a novel family of non-B, non-T cell lymphocytes that was established within the last decade(Spits et al, 2013; Vivier et al, 2018)
A central purpose of the present study was to characterize group 1 ILC in cord blood (CB), which provides a rich source for ILCs comprising all three ILC subsets as well as both major natural killer (NK) cell subsets, the regulatory CD56bright and the cytotoxic CD56dim NK cells(Bennstein et al, 2019). To this end, ILC1-like cells, defined as lin-CD94-CD127+CRTH2-CD117- cells, CD56bright NK cells, and CD56dim NK cells were flow cytometrically sorted from freshly collected CB and subjected to RNAseq analysis (Fig. S1)
We demonstrate that ILC1-like cells can be broken down into two subsets, a major CD5+CD161-/+ subset expressing the chemokine receptors CCR7, CCR4, and CCR9 and failing to secrete IFNγ and a small CD5-CD161+ subset not expressing any of the three chemokine receptors but showing IFNγ secretion after specific stimulation

Summary

Introduction

Innate lymphoid cells (ILC) constitute a novel family of non-B, non-T cell lymphocytes that was established within the last decade(Spits et al, 2013; Vivier et al, 2018). 82 Regarding the developmental relationship between human NK cells and ILC1, recent data support the existence of separate precursors for the development of ILC1 and NK cells downstream of the common lymphoid progenitor stage(Renoux et al, 2015; Vivier et al, 2018), which is a revision of the initial model assuming a direct common progenitor of ILC1 and NK cells(Spits et al, 2013). Several studies in mice suggest a conversion of NK cells into ILC1(Cortez et al, 2017; Park et al, 2019) It is currently not known if ILC1 can be converted into NK cells, except by reprogramming of murine ILC1 with Eomes, a central TF for NK cell development and maturation(Pikovskaya et al, 2016). Plasticity between NK and ILC1s has so far not been shown in humans

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