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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 barriers. 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 properties, 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 development, by using lineage tracing and transfer studies. PLZF^sup high^ 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^sup +^DX5^sup -^ 'NK-like' cells residing in the liver. Deletion of PLZF markedly altered the development of several ILC subsets, but not LTi or NK cells. PLZF^sup high^ precursors also expressed high amounts of ID2 and GATA3, as well as TOX, a known regulator of PLZF-independent NK and LTi lineages. These findings establish novel lineage rela- tionships between ILC, NK and LTi cells, and identify the common precursor to ILCs, termed ILCP. They also reveal the broad, defin- ing role of PLZF in the differentiation of innate lymphocytes.
To study the expression pattern of Zbtb16 encoding the transcrip- tion factor PLZF, which directs the developmental acquisition of the innate effector program of NK T cells11,12,14,15, we inserted a sequence coding for a fusion of enhanced green fluorescent protein (GFP) and Cre downstream of an IRES after the last exon of Zbtb16 (Extended Data Fig. 1a). As expected, GFP was selectively expressed in the NK T lineage, with early developmental stages 1 and 2 showing higher levels than mature stage 3 cells, but was not found in the bone marrow com- mon lymphoid precursor (CLP), T cells or B cells of PLZFGFPcre1/2 mice (Fig. 1a). In PLZFGFPcre1/2 mice carrying the ROSA26-floxstop- yellow fluorescent protein (YFP) fate-mapping allele, nearly all NK T cells expressed YFP, as expected, although approximately 35% of cells in all lymphoid and myeloid lineages werealso...