Type-2 innate lymphoid cells in human allergic disease

Abstract

Purpose of review: Recent decades have seen allergic diseases become endemic in a number of developed countries. Understanding the inflammatory processes that dictate these allergic responses is therefore important.

Recent findings: Critical to many allergic responses is the inappropriate release of the type-2 immune-regulatory cytokines: interleukin-4, interleukin-5, interleukin-9, and interleukin-13. The study of these inflammatory mediators has led directly to the development of two new asthma treatments: anti-interleukin-5 and anti-interleukin-13. Until recently, T helper 2 cells were considered to be the major cellular source of type-2 cytokines; however, a paradigm shift occurred with the discovery of a novel population, type-2 innate lymphoid cells (ILC2s), that can produce huge levels of type-2 cytokines and are sufficient to induce allergy in mice. This discovery raises interesting questions about how innate and adaptive type-2 immunity might interact to induce relapsing and remitting episodes of allergy in patients.

Summary: It is essential that alongside the mechanistic investigation using model organisms, the roles of ILC2s in human disease be explored. Here, we discuss how ILC2 traits, discovered in mouse models, have informed research in humans and how newly identified human ILC2 pathways might provide potential therapeutic benefits in the future.

FIGURE 1

A nomenclature for the ILCs. Innate cells from the lymphoid lineage, that is, those that do not express T-cell receptor (TCR), have now been classified as group 1 ILCs containing ILC1s and NK cells, group 2 ILCs, and group 3 ILCs containing ILC3s and LTi cells. They are all defined by their cell-surface marker expression, transcriptional regulation, and cytokine signature. Early studies have also begun to define what types of immune response each cell type is associated with.

Box 1

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FIGURE 2

Soluble modifiers of ILC2 effector functions during allergy. Following allergen challenge at the mucosal surface release of IL-25, IL-33 and TSLP have been shown to influence ILC2 expansion and the production of the archetypal type-2 cytokines: IL-4, IL-5, and IL-13. Recently, other soluble factors such as TL1A and PGD2 have also been implicated in ILC2 activation. AA, alternatively activated; CRTH2, prostaglandin D2 receptor; IL, interleukin; LTD4, leukotriene D4; LXA4, lipoxin A4; R, receptor; Th, T helper; TSLP, thymic stromal lymphopoietin; TL1A, TNF-like ligand 1A.