The role of rare innate immune cells in Type 2 immune activation against parasitic helminths

Abstract

The complexity of helminth macroparasites is reflected in the intricate network of host cell types that participate in the Type 2 immune response needed to battle these organisms. In this context, adaptive T helper 2 cells and the Type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have been the focus of research for years, but recent work has demonstrated that the innate immune system plays an essential role. Some innate immune cells that promote Type 2 immunity are relatively abundant, such as macrophages and eosinophils. However, we now appreciate that more rare cell types including group 2 innate lymphoid cells, basophils, mast cells and dendritic cells make significant contributions to these responses. These cells are found at low frequency but they are specialized to their roles - located at sites such as the skin, lung and gut, where the host combats helminth parasites. These cells respond rapidly and robustly to worm antigens and worm-induced damage to produce essential cytokines, chemokines, eicosanoids and histamine to activate damaged epithelium and to recruit other effectors. Thus, a greater understanding of how these cells operate is essential to understand how the host protects itself during helminth infection.

Keywords: ILC2; Type 2; basophil; dendritic; helminth; innate; mast cell; mucosal.

Figure 1. Innate immune cells participate in a network that facilitates anti-helminth Type 2 immunity

Worms cause significant damage to the epithelium as they migrate and complete their lifecycle. This causes release of damage signals such as interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP) that promote the activation of innate cells present in the tissue. Activated DCs sense antigen (Ag) and migrate to the draining lymph node (dLN), where they release pro-Th2 mediators such as Type I interferon (IFN-I), CCL17 and Relmα and induce polarization of naïve T cells to a T helper 2 (Th2) cell fate. Tissue-released damage signals also activate basophils, ILC2s and MCs that play distinct roles in the tissue. Basophils produce various inflammatory mediators such as chemokines and histamine and may interact with ILC2s. ILC2s are rich sources of Type 2 cytokines and wound repair-related molecules (not shown). Activated MCs release inflammatory mediators including prostaglandin D₂ (PGD₂), which activates and recruits ILC2s. Critically, activated basophils, ILC2s and MCs produce significant amounts of IL-4, IL-5 and IL-13 that can contribute to the polarization of Th2 cells in the dLN and may potentiate the activity of Th2 cells within the tissue. Finally, Type 2 cytokines from these innate cells and activated Th2 cells in the tissue recruit eosinophils, induce the alternative activation of macrophages (AAMΦ) that produce anti-helminth and pro-wound healing mediators such as Relmα, and activate anti-helminth responses from the epithelium, such as goblet cell hyperplasia, mucus production, tuft cell activation and epithelial cell turnover.