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Mucosal Immunol. 2020 Mar;13(2):257-270. doi: 10.1038/s41385-019-0220-y. Epub 2019 Nov 11.

Single-cell RNA-sequencing identifies the developmental trajectory of C-Myc-dependent NK1.1- T-bet+ intraepithelial lymphocyte precursors.

Author information

1
Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, 79104, Freiburg, Germany.
2
Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany.
3
Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104, Freiburg, Germany.
4
International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany.
5
Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, 79104, Freiburg, Germany.
6
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, 79104, Freiburg, Germany.
7
CIBSS - Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
8
Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, 79104, Freiburg, Germany. yakup.tanriver@uniklinik-freiburg.de.
9
Department of Internal Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany. yakup.tanriver@uniklinik-freiburg.de.

Abstract

Natural intraepithelial lymphocytes (IELs) are thymus-derived adaptive immune cells, which are important contributors to intestinal immune homeostasis. Similar to other innate-like T cells, they are induced in the thymus through high-avidity interaction that would otherwise lead to clonal deletion in conventional CD4 and CD8 T cells. By applying single-cell RNA-sequencing (scRNA-seq) on a heterogeneous population of thymic CD4-CD8αβ-TCRαβ+NK1.1- IEL precursors (NK1.1- IELPs), we define a developmental trajectory that can be tracked based on the sequential expression of CD122 and T-bet. Moreover, we identify the Id proteins Id2 and Id3 as a novel regulator of IELP development and show that all NK1.1- IELPs progress through a PD-1 stage that precedes the induction of T-bet. The transition from PD-1 to T-bet is regulated by the transcription factor C-Myc, which has far reaching effects on cell cycle, energy metabolism, and the translational machinery during IELP development. In summary, our results provide a high-resolution molecular framework for thymic IEL development of NK1.1- IELPs and deepen our understanding of this still elusive cell type.

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