Volume 31, No 5, May 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 5, May 2021: 554-568   |  Open Access

ORIGINAL ARTICLES

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

Luca Mazzurana¹ , Paulo Czarnewski² , Viktor Jonsson³ , Leif Wigge³ , Markus Ringnér⁴ , Teresa C. Williams¹ , Avinash Ravindran⁵ , Åsa K. Björklund⁶ , Jesper Säfholm⁷ , Gunnar Nilsson⁵ , Sven-Erik Dahlén⁷ , Ann-Charlotte Orre⁸ , Mamdoh Al-Ameri^8,9 , Charlotte Höög¹⁰ , Charlotte Hedin^10,11 , Sylwester Szczegielniak¹¹ , Sven Almer^10,11 , Jenny Mjösberg^1,*

¹Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden
²Science for Life Laboratory, Department of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden, Stockholm University, Solna, Sweden
³Science for Life Laboratory, Department of Biology and Biological Engineering, National Bioinformatics Infrastructure Sweden, Chalmers University of Technology, Gothenburg, Sweden
⁴Science for Life Laboratory, Department of Biology, National Bioinformatics Infrastructure Sweden, Lund University, Lund, Sweden
⁵Immunology and Allergy Unit, Department of Medicine Solna, Department of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
⁶Science for Life Laboratory, Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Uppsala University, Uppsala, Sweden
⁷Institutet of Environmental Medicine, Center for Allergy Research, Karolinska Institutet, Stockholm, Sweden
⁸Division of Thoracic Surgery, Karolinska University Hospital, Stockholm, Sweden
⁹Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
¹⁰Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
¹¹Division of Gastroenterology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
Correspondence: Jenny Mjösberg(jenny.mjosberg@ki.se)

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.

https://doi.org/10.1038/s41422-020-00445-x

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