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

Nature. 2016 Nov 3;539(7627):102-106. doi: 10.1038/nature20105. Epub 2016 Sep 29.

Abstract

Innate lymphoid cells (ILCs) functionally resemble T lymphocytes in cytotoxicity and cytokine production but lack antigen-specific receptors, and they are important regulators of immune responses and tissue homeostasis. ILCs are generated from common lymphoid progenitors, which are subsequently committed to innate lymphoid lineages in the α-lymphoid progenitor, early innate lymphoid progenitor, common helper innate lymphoid progenitor and innate lymphoid cell progenitor compartments. ILCs consist of conventional natural killer cells and helper-like cells (ILC1, ILC2 and ILC3). Despite recent advances, the cellular heterogeneity, developmental trajectory and signalling dependence of ILC progenitors are not fully understood. Here, using single-cell RNA-sequencing (scRNA-seq) of mouse bone marrow progenitors, we reveal ILC precursor subsets, delineate distinct ILC development stages and pathways, and report that high expression of programmed death 1 (PD-1hi) marked a committed ILC progenitor that was essentially identical to an innate lymphoid cell progenitor. Our data defined PD-1hiIL-25Rhi as an early checkpoint in ILC2 development, which was abolished by deficiency in the zinc-finger protein Bcl11b but restored by IL-25R overexpression. Similar to T lymphocytes, PD-1 was upregulated on activated ILCs. Administration of a PD-1 antibody depleted PD-1hi ILCs and reduced cytokine levels in an influenza infection model in mice, and blocked papain-induced acute lung inflammation. These results provide a perspective for exploring PD-1 and its ligand (PD-L1) in immunotherapy, and allow effective manipulation of the immune system for disease prevention and therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Base Sequence*
  • Cell Differentiation
  • Cell Lineage* / genetics
  • Cell Separation
  • Cytokines / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Humans
  • Immunity, Innate*
  • Immunotherapy / trends
  • Influenza, Human / immunology
  • Influenza, Human / metabolism
  • Killer Cells, Natural / cytology
  • Lymphocyte Activation
  • Lymphocytes / cytology*
  • Lymphocytes / immunology
  • Lymphocytes / metabolism
  • Lymphoid Progenitor Cells / cytology*
  • Lymphoid Progenitor Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Pneumonia / immunology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism*
  • Receptors, Interleukin / metabolism
  • Repressor Proteins / deficiency
  • Repressor Proteins / metabolism
  • Single-Cell Analysis*
  • T-Lymphocytes / metabolism
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / metabolism

Substances

  • Antibodies
  • Bcl11b protein, mouse
  • Cytokines
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Interleukin
  • Repressor Proteins
  • Tumor Suppressor Proteins