Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells

Innate lymphoid cells (ILCs) serve as sentinels in mucosal tissues, sensing release of soluble inflammatory mediators, rapidly communicating danger via cytokine secretion, and functioning as guardians of tissue homeostasis. Although ILCs have been extensively studied in model organisms, little is known about these “first responders” in humans, especially their lineage and functional kinships to cytokine-secreting T helper (Th) cell counterparts. Here, we report gene regulatory circuitries for four human ILC-Th counterparts derived from mucosal environments, revealing that each ILC subset diverges as a distinct lineage from Th and circulating natural killer cells but shares circuitry devoted to functional polarization with their Th counterparts. Super-enhancers demarcate cohorts of cell-identity genes in each lineage, uncovering new modes of regulation for signature cytokines, new molecules that likely impart important functions to ILCs, and potential mechanisms for autoimmune disease SNP associations within ILC-Th subsets. [Display omitted] •Regulomes and gene expression establish distinct lineages for ILC, Th, and NK cells•ILC-Th counterparts share some, but not all, circuitry for functional polarization•Coordinately regulated enhancers reveal transcription factors for ILC-Th programs•ILC-Th super-enhancers identify new functional and regulatory modes Integrative “omics” analyses reveal lineage and functional distinctions between human ILCs and their T-helper counterparts, especially with respect to regulatory elements called super-enhancers, which drive expression of cell-identity genes.