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

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 gut 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-d rearrangement. In summary, we provide publicly available data as a resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease. Overall design: In this study, we analyzed human ILCs through full-length scRNAseq, combining data from four different tissues: peripheral blood from three healthy donors, lung tissue from four patients undergoing lobectomy for lung cancer, and biopsies from the ascending colon obtained from three tumor-screening patients with known genetic predisposition for colon cancer but without any polyps or tumors at the time of sampling. The previously published tonsil data was also used in this study and can be found at GEO: GSE70580 (all GSMs); Sequence Read Archive: SRP060416. >>>Submitter declares that the raw data for non-tonsil samples will be deposited in EGA due to patient privacy concerns.<<<