Shaping Innate Lymphoid Cell Diversity

Abstract

Innate lymphoid cells (ILCs) are a key cell type that are enriched at mucosal surfaces and within tissues. Our understanding of these cells is growing rapidly. Paradoxically, these cells play a role in maintaining tissue integrity but they also function as key drivers of allergy and inflammation. We present here the most recent understanding of how genomics has provided significant insight into how ILCs are generated and the enormous heterogeneity present within the canonical subsets. This has allowed the generation of a detailed blueprint for ILCs to become highly sensitive and adaptive sensors of environmental changes and therefore exquisitely equipped to protect immune surfaces.

Keywords: differentiation; gene expression; immune protection; innate immunity; innate lymphoid cell.

Figure 1

Overview of stages of innate lymphoid cell (ILC) development. (A) Current understanding of the regulation of peripheral ILC subsets. A variety of different transcription factors are required for the development of peripheral ILC subsets. Key transcription factors (red) are responsible for the lineage determination of the canonical ILC subsets (top panel). ILC subsets can also be further differentiated and categorized based on the organ in which they reside, functional differences, or the expression of different receptors and surface markers (middle panel). In response to activation signals, ILCs are able to produce effector molecules and cytokines to mediate an appropriate immune response (bottom panel). (B) Schematic showing the current understanding of ILC development from the common lymphoid progenitor (CLP) through multiple intermediary stages on their way to becoming mature ILC subsets ILC1, 2, and 3. CLP has multi-lineage potential, including T and B cell fate, but this potential is gradually lost as the progenitors differentiate into the more lineage restricted αLP. This occurs through the intermediate α4β7⁺ CLP and αLP/common helper-like ILC precursor (CHILP) progenitors or through an alternative pathway via the early innate lymphoid progenitors (EILPs). Within the αLP population, the natural killer (NK) cell lineage diverges from the ILC lineage and the ILC precursor (ILCp) exclusively develops into the remaining mature ILCs in the periphery. (C) Dynamic regulation of the surface markers (left panel) and transcription factors (right panel) throughout the ILC ontogeny. The graphs show the relative RNA expression among the different ILC progenitor stages (100% represents the highest expression for each gene detected across the six different populations).

Figure 2

Heterogeneity and plasticity are prominent features of innate lymphoid cell (ILC) behavior across all subsets. (A) Deep analysis into the transcriptome of ILCs demonstrates that heterogeneity occurs within every subset. Depending on the type or intensity of the stimuli received by these cells, different molecular pathways may be activated by cells of the same subset. This results in phenotypic or functional variation and a subsequent spectrum of ILCs within each compartment. Whether additional subsets such as the proposed regulatory subset exist is yet to be fully determined. (B) ILC3s can adopt an ILC1-like phenotype when activated by IL-12. They are known as “ex-ILC3s.” In human cells, this pathway can be reversed by the action of IL-23, IL-2, and IL-1β. ILC2s are activated by IL-2 and IL-33. Stimulation with IL-1β primes the responsiveness of ILC2 by enhancing the expression of cytokine receptors such as IL-25R, IL-33R, and TSLP to potentiate ILC2 responsiveness and induce a significant increase in the population. Critically, however, IL-12 is essential to effect remodeling of the chromatin landscape in ILC2 allowing them to induce phenotypic changes and become more like ILC1s (ILC1-like or “ex-ILC2s”) that produce IFN-γ. Natural killer (NK) cells respond to TGF-β to form “intermediate ILC1” reflecting their acquisition of CD49a and bone fide ILC1. In many situations, it appears that the transcription factor T-bet is key to augmentation of the inflammatory program and concurrently represses signature transcription factors that typically define individual lineages.