Type 2 innate lymphoid cells: at the cross-roads in allergic asthma

Abstract

Allergic asthma is a chronic inflammatory disease of the lower airways that affects millions of people worldwide. Allergic asthma is a T helper 2 cell (Th2)-mediated disease, in which Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 are closely associated with the symptoms. IL-4 is needed by B cells to switch toward an IgE response, IL-5 recruits and activates eosinophils while IL-13 increases mucus production. The identification of type 2 innate lymphoid cells (ILC2), which are able to rapidly produce large amounts of IL-5 and IL-13 in response to epithelial derived cytokines, implicated a new key player besides Th2 cells. ILCs constitute a family of innate lymphocytes distinct from T and B cells. ILC2s are located in various epithelial compartments in mice and human, including the lung. The recent finding of increased numbers of ILC2s in the airways of severe asthma patients prompts further research to clarify their immunological function. Murine studies have shown that ILC2s are an early innate source of IL-5 and IL-13 after allergen exposure, which induce airway eosinophilic infiltration, mucus hyperproduction, and airway hyperresponsiveness but not allergen-specific IgE production. ILC2s contribute to the initiation as well as to the maintenance of the adaptive type 2 immune response. Here, we review the recent progress on our understanding of the role of ILC2s in the immunopathology of allergic asthma, in particular by studies using murine models which have elucidated fundamental mechanisms by which ILC2s act.

Keywords: Allergic asthma; Type 2 immune response; Type 2 innate lymphoid cells.

Fig. 1

ILC2 interactions in allergic asthma. The inbetweeners: ILC2s in the immunopathology of allergic asthma. ILC2s respond to IL-25, IL-33, or TSLP, which is produced by airway epithelial cells in response to allergen encounter or infection with helminthes or viruses. In addition, ILC2s may be activated by innate cell-derived PGD₂, LTD₄, TL1A, IL-25, or IL-33. IL-9 activates ILC2s in an autocrine manner. The production of IL-5 and IL-13 by ILC2s contributes to typical allergic asthma hallmarks, including pulmonary eosinophilia, mucus hyperproduction, and AHR. ILC2-derived IL-13 was shown to induce accumulation of alternatively activated macrophages and promote migration of DCs from the lung to lymph node. ILC2s also interact with T cells, likely via MHCII expression and possibly via expression of IL-4 and OX40L. In turn, T cells can activate ILC2s by secreting IL-2. In addition, ILC2s may interact with B cells, possibly via expression of ICOS-ligand or IL-4. The presence of ILC2s might also have beneficial effects in allergic asthma, as their production of amphiregulin (Areg) was shown to promote tissue repair of the epithelium in pulmonary inflammation