|SHIH, HAN-YU - National Institutes Of Health (NIH)|
|SCIUME, GIUSEPPE - National Institutes Of Health (NIH)|
|MIKAMI, YOHEI - National Institutes Of Health (NIH)|
|GUO, LIYING - National Institutes Of Health (NIH)|
|SUN, HONG-WEI - National Institutes Of Health (NIH)|
|BROOKS, STEPHEN - National Institutes Of Health (NIH)|
|DAVIS, FRED - National Institutes Of Health (NIH)|
|KANNO, YUKA - National Institutes Of Health (NIH)|
|O'SHEA, JOHN - National Institutes Of Health (NIH)|
Submitted to: Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/19/2016
Publication Date: 5/19/2016
Citation: Shih, H., Sciume, G., Mikami, Y., Guo, L., Sun, H., Brooks, S.R., Urban Jr, J.F., Davis, F.P., Kanno, Y., O'Shea, J.J. 2016. Developmental acquisition of regulomes underlies innate lymphoid cell functionality. Cell. 165:1120-1133. doi: 10.1016/j.cell.2016.04.029.
Interpretive Summary: Helminth (worm) infections are a global health concern in livestock as well as humans because they establish chronic and repeated infections. The characterization of immune cells that are part of the innate immune response, i.e., those that are activated in a naive host not previously infected, has stimulated interest in the role of innate cells versus the better known adaptive T helper cells in immunity to worm parasites. Innate lymphoid cells (ILC) and adaptive cells become specialized to produce cytokines or protein messenger molecules by distinct routes. Characterization of cellular chromatin regions or accessible genes in the cell that lead to ILC effector function revealed regulatory circuits that are shared by innate and adaptive cells. Regulatory elements (RE) were identified that comprise the cell lineage-specific "regulome" of prototypical ILCs and their progenitors. Genome-wide analysis revealed that each ILC lineage possessed unique open chromatin regions that were similar in distinct lineages of all ILC populations. These features were relatively static after ILC activation indicating that ILCs are committed prior to stimulation. In contrast, naive T cells exhibit markedly different chromatin regions that change dramatically after activation and during differentiation. The substantial overlap of REs between T helper and ILCs is notable given their distinct routes of development. The data provided mechanistic details of ILC lineage commitment, the acquisition of functional properties, and the relationships between innate and adaptive cells in the immune system. This information will inform scientists interested in developing useful and safe procedures to protect humans and livestock from parasitic infection and allergic disease.
Technical Abstract: Innate lymphoid cells (ILCs) play key roles in host defense, barrier integrity, and homeostasis, and they mirror adaptive CD4+ T helper (Th) cell subtypes in both usages of effector molecules and ·transcription factors. To better understand ILC subsets and their relationship with Th cells, we measured genome-wide chromatin accessibility. We found that chromatin in proximity to effector genes was selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions was acquired in a stepwise manner during development and changed little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurred in naive CD4+ T cells during Th cell differentiation using a type 2-infection model. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways.