A committed precursor to innate lymphoid cells

Abstract

A committed precursor to innate lymphoid cell lineages, but not classical natural killer and lymphoid tissue inducer cells, is derived from common lymphoid precursors and distinguished by high levels of expression of the transcription factor PLZF. Knowledge of the developmental pathways and lineage relationships of the precursors to innate lymphocytes is important because these cells serve key protective functions in infection and homeostasis at mucosal barriers, and because of their crosstalk with epithelium and microbiota. This study identifies a committed common lymphoid-derived precursor to innate lymphoid cell (ILC) lineages. The progenitor cells, termed ILCPs (innate lymphoid cell precursors), are distinct from classical natural killer (NK) and lymphoid tissue inducer cells, thus demonstrating that similar functional programs arise independently in different lineages of innate lymphocytes. The findings also imply the presence of highly specialized innate lymphoid lineages within what was previously regarded as a broader NK-cell population. Innate lymphoid cells (ILCs) specialize in the rapid secretion of polarized sets of cytokines and chemokines to combat infection and promote tissue repair at mucosal barriers1,2,3,4,5,6,7,8,9. Their diversity and similarities with previously characterized natural killer (NK) cells and lymphoid tissue inducers (LTi) have prompted a provisional classification of all innate lymphocytes into groups 1, 2 and 3 solely on the basis of cytokine properties10, but their developmental pathways and lineage relationships remain elusive. Here we identify and characterize a novel subset of lymphoid precursors in mouse fetal liver and adult bone marrow that transiently express high amounts of PLZF, a transcription factor previously associated with NK T cell development11,12, by using lineage tracing and transfer studies. PLZFhigh cells were committed ILC progenitors with multiple ILC1, ILC2 and ILC3 potential at the clonal level. They excluded classical LTi and NK cells, but included a peculiar subset of NK1.1+DX5− ‘NK-like’ cells residing in the liver. Deletion of PLZF markedly altered the development of several ILC subsets, but not LTi or NK cells. PLZFhigh precursors also expressed high amounts of ID2 and GATA3, as well as TOX, a known regulator of PLZF-independent NK and LTi lineages13. These findings establish novel lineage relationships between ILC, NK and LTi cells, and identify the common precursor to ILCs, termed ILCP. They also reveal the broad, defining role of PLZF in the differentiation of innate lymphocytes.