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

Y Yu, JCH Tsang, C Wang, S Clare, J Wang, X Chen… - Nature, 2016 - nature.com
Y Yu, JCH Tsang, C Wang, S Clare, J Wang, X Chen, C Brandt, L Kane, LS Campos, L Lu…
Nature, 2016nature.com
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 …
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.
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