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Innate lymphoid cells (ILCs) are a recently identified subset of the innate immune system found to have transformative roles in integrating innate and adaptive immune responses. In a wide distribution of tissues, ILCs are important sources of cytokines that promote inflammation, host defense against infection, tissue repair, regulation of microbiota, and physiological homeostasis. As a newly appreciated lineage, many aspects of ILC development and differentiation are not well understood. The Bendelac lab recently identified a common ILC precursor (ILCP) in the fetal liver and bone marrow on the basis of expression of PLZF, the NKT master regulator. The ILCP gives rise to all ILC lineages, including ILC1, ILC2, and ILC3, but not LTi or NK. The developmental stages and associated regulatory factors surrounding the emergence and differentiation of the ILCP have yet to be defined. We present three experimental designs that probe transcriptional regulation in ILC precursors. First we use genome-wide expression profiling to describe the role PLZF plays in distinguishing cNK and ILC1 lineages. Next we performed computational clustering of single ILC progenitor expression profiles to establish a hierarchy of ILC development and found: 1) There is a specific developmental progression of transcription factor induction upstream of the ILCP. 2) ILC differentiation occurs after acquisition of PLZF in the ILCP. 3) LTi specification immediately precedes ILC differentiation and is a distinct lineage decision. 4) ILC differentiation occurs through multilineage transcriptional priming. Finally, we compared chromatin accessibility transcriptional profiling in the ILPC to identify the predominant transcriptional regulators affiliated with ILC specification. The precise elaboration of ILC developmental stages and identification of novel ILC developmental regulators will improve our understanding of the functional requirements of ILCs and their roles in immunity.


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