Therapeutic manipulation of innate lymphoid cells
Laura M. Cobb, Michael R. Verneris
Laura M. Cobb, Michael R. Verneris
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Review

Therapeutic manipulation of innate lymphoid cells

Abstract

Since their relatively recent discovery, innate lymphoid cells (ILCs) have been shown to be tissue-resident lymphocytes that are critical mediators of tissue homeostasis, regeneration, and pathogen response. However, ILC dysregulation contributes to a diverse spectrum of human diseases, spanning virtually every organ system. ILCs rapidly respond to environmental cues by altering their own phenotype and function as well as influencing the behavior of other local tissue-resident cells. With a growing understanding of ILC biology, investigators continue to elucidate mechanisms that expand our ability to phenotype, isolate, target, and expand ILCs ex vivo. With mounting preclinical data and clinical correlates, the role of ILCs in both disease pathogenesis and resolution is evident, justifying ILC manipulation for clinical benefit. This Review will highlight areas of ongoing translational research and critical questions for future study that will enable us to harness the full therapeutic potential of these captivating cells.

Authors

Laura M. Cobb, Michael R. Verneris

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Figure 2

Targeting ILCs in obesity and type 2 diabetes mellitus.

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Targeting ILCs in obesity and type 2 diabetes mellitus. In healthy white...
In healthy white adipose (A), ILC2s promote an antiinflammatory type 2 environment via eosinophil recruitment and induction of alternatively activated macrophages (AAMs). Specialized beige adipocytes interspersed in WAT can utilize the mitochondrial uncoupling protein 1 (UCP1) for thermogenesis, increasing caloric expenditure and protecting from obesity. “Beiging” is promoted by ILC2 production of methionine-enkephalin (MetEnk) peptides. Thus, expansion of ILC2s via IL-25, IL-33, or ILC2 adoptive transfer promotes weight loss and improved glucose tolerance. Additionally, engagement of the glucocorticoid-induced TNF receptor (GITR) on ILC2s via a GITR agonist also promotes beiging. ILC2s are decreased in obese adipose (B), while ILC1s are increased. IL-12–dependent IFN-γ production is sustained by adipose ILC1s and induces classically activated macrophages (CAMs) to secrete IL-6 and TNF-α. This promotes a proinflammatory type 1 environment, which fosters development of glucose intolerance and leads to type 2 diabetes mellitus. Therefore, therapeutically activating the IL-33/GITR/ILC2-beiging pathway signifies a novel method for treating obesity and T2DM. Illustrated by Rachel Davidowitz.