Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells

Abstract

SUMMARY 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 studied extensively 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.

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

“…Gene expression data were transformed into Z‐score values by genes across samples for presentation. The list of human Th17‐ or ILC3‐related genes and IL‐22 signaling (responsive) genes were retrieved from previous reports 29, 30, 31, 32…”

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

“…The second group consists of genes that are normally not activated to substantial levels at all during the phase 1 stages. Curiously, these are highly enriched for genes used in NK cells, ILCs, and innate-like T cells, including the powerful regulatory genes Id2, Zbtb16, and Nfil3 (6,42,(49)(50)(51)(52)(53)(54)(55). Many of these genes, especially NK-associated genes, require continual Bcl11b action to keep them silent later (Fig.…”

“…Indeed, the Kyoto Encyclopedia of Genes and Genomes pathway most highly enriched in our Bcl11b-repressed gold-standard gene set was NK cell-mediated cytotoxicity (SI Appendix, Fig. S6A), and multiple genes were shared with gene sets that distinguish ILC from T cells (42,43). However, the gold-standard set as a whole was distinct from top Bcl11b-regulated genes in DP cells.…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Recent high‐resolution epigenetic and transcriptomic analyses of human and murine ILC3 have begun to clarify subset‐specific functional and transcriptional phenotypes, while revealing that ILC3 exhibit a higher degree of plasticity and heterogeneity than previously appreciated 56, 57, 58, 59, 60. Despite sharing many overlapping transcriptional pathways LTi‐like and NKp46 + ILC3 subsets exhibit considerable differences in chromatin accessibility and predicted transcription factor occupancy among accessible gene regulatory elements 58, 59, 60. Differences between these two canonical ILC3 subsets are further highlighted on the transcriptional level 56, 60.…”