Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing
Luca Mazzurana, Paulo Czarnewski, Viktor Jönsson, Leif Wigge, Markus Ringnér, Teresa C. Williams, Avinash Ravindran, Åsa K. Björklund, Jesper Säfholm, Gunnar Nilsson, Sven-Erik Dahlén, Ann‐Charlotte Orre, Mamdoh Al‐Ameri, Charlotte Höög, Charlotte Hedin, Sylwester Szczegielniak, Sven Almér, Jenny Mjösberg
Abstract
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.