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Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its developmental pathway

last modified Sep 29, 2016 05:40 PM
Yong Yu, Jason C.H. Tsang, Cui Wang, Simon Clare, Juexuan Wang, Xi Chen, Cordelia Brandt, Leanne Kane, Lia S. Campos, Liming Lu, Gabrielle T. Belz, Andrew N. J. McKenzie, Sarah A. Teichmann, Gordon Dougan & Pentao Liu

Abstract

Innate lymphoid cells (ILCs) functionally resemble T lymphocytes in cytotoxicity and cytokine production but lack antigen-specific receptors, and are important regulators in immune response and tissue homeostasis1, 2. ILCs are generated from common lymphoid progenitors (CLPs), which are subsequently committed to innate lymphoid lineages in the α lymphoid progenitor (αLP), early innate lymphoid progenitor (EILP), common helper innate lymphoid progenitor (CHILP) and innate lymphoid cell progenitor (ILCP) compartments3, 4, 5, 6, 7, 8. ILCs consist of conventional NK (cNK), and helper-like cells: ILC1, ILC2 and ILC3 (ref. 9). Despite recent advances1, 2 10, the cellular heterogeneity, developmental trajectory and signalling dependence of ILC progenitors remain incompletely understood. Here we report that single-cell RNA-sequencing (scRNAseq) of bone marrow (BM) progenitors revealed ILC precursor subsets, delineated distinct ILC development stages and pathways, and uncovered that programmed death 1 high expression (PD-1hi) marked a committed ILC progenitor that was essentially identical to ILCP. Our data defined PD-1hiIL-25Rhi as an early checkpoint in ILC2 development, which was abolished by Bcl11b-deficiency but restored by IL-25R overexpression. Similar to T lymphocytes, PD-1 was up-regulated on activated ILCs. Administration of a PD-1 antibody depleted PD-1hi ILCs and reduced cytokine levels in an influenza infection model, and blocked papain-induced acute lung inflammation. These results provide a novel perspective for exploring PD-1/PD-L1 in immunotherapy, and allow effective manipulation of the immune system for disease prevention and therapy.

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