Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing

Luca Mazzurana,Teresa C Williams,Sylwester Szczegielniak,Markus Ringnér,Charlotte Hedin,Sven Almer,Mamdoh Al-Ameri,Viktor Jonsson,Paulo Czarnewski,Leif Wigge,Sven-Erik Dahlén,Gunnar Nilsson,Avinash Ravindran,Jesper Säfholm,Jenny Mjösberg,Ann-Charlotte Orre,Charlotte Höög,Åsa K Björklund

doi:10.1038/s41422-020-00445-x

Abstract

The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown. Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127+ ILCs across four human tissues. Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs, and signatures of tissue-residency, activation and modified metabolism in colon and lung ILCs. Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident naïve ILCs to a spectrum of mature ILC subsets. In the lung we identified both CRTH2+ and CRTH2− ILC2 with lung-specific signatures, which could be recapitulated by alarmin-exposure of circulating ILC2. Finally, we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells, revealing a subset of potentially immature ILCs with TCR-δ rearrangement. Our study provides a useful resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease.

Highlights

Innate lymphoid cells (ILCs) are a recent addition to innate immunity, playing an important role in clearing intra- and extracellular pathogens, regulating adaptive immunity, tissue repair and contributing to inflammation.[1]
Recirculating CD56dimCD16+ Natural killer (NK) cells were sorted from the lung[13] and predominantly tissueresident NK cells were sorted as bulk CD56+ from the gut[14] or as CD56brightNKG2A+ NK cells from the tonsil.[12]
Previous reports have described tissue-specific transcriptional imprinting of ILCs across multiple organs. These findings originated from pre-defined ILC subsets sorted in bulk from mice[2] or humans,[3] neglecting heterogeneity in the sorted populations

Summary

Introduction

Innate lymphoid cells (ILCs) are a recent addition to innate immunity, playing an important role in clearing intra- and extracellular pathogens, regulating adaptive immunity, tissue repair and contributing to inflammation.[1] Their defining feature is a lack of rearranged antigen-specific receptors, which distinguishes them from T cells. In other ways these cells closely mirror the function of their adaptive counterparts, being an essential source of cytokines related to type 1, 2 and 17 immune responses.[1] Currently, ILCs are classified into five subsets: ILC1, ILC2, ILC3, Natural killer (NK). Cells and lymphoid tissue inducer (LTi) cells. ILC1 produce interferongamma (IFN-γ) and are dependent on the T-box transcription factor (TF) TBX21 (Tbet) for their development and function. NK cells share these features with ILC1, but they express the TF

Methods

Results

Conclusion