ILC2s-Trailblazers in the Host Response Against Intestinal Helminths

Abstract

Group 2 innate lymphoid cells (ILC2s) were first discovered in experimental studies of intestinal helminth infection-and much of our current knowledge of ILC2 activation and function is based on the use of these models. It is perhaps not surprising therefore that these cells have also been found to play a key role in mediating protection against these large multicellular parasites. ILC2s have been intensively studied over the last decade, and are known to respond quickly and robustly to the presence of helminths-both by increasing in number and producing type 2 cytokines. These mediators function to activate and repair epithelial barriers, to recruit other innate cells such as eosinophils, and to help activate T helper 2 cells. More recent investigations have focused on the mechanisms by which the host senses helminth parasites to activate ILC2s. Such studies have identified novel stromal cell types as being involved in this process-including intestinal tuft cells and enteric neurons, which respond to the presence of helminths and activate ILC2s by producing IL-25 and Neuromedin, respectively. In the current review, we will outline the latest insights into ILC2 activation and discuss the requirement for-or redundancy of-ILC2s in providing protective immunity against intestinal helminth parasites.

Keywords: ILC2; activation; helminth; neuron; regulation; tuft cell; type 2 immunity.

Figure 1

In response to various stimuli such as infection or injury, mucosal epithelial barriers express a range of signals that ILC2s can integrate. The most studied and thought to be of utmost importance pathway of activation of ILC2 is formed by the “alarmins,” IL-33, TSLP, and IL-25 that cause release of the canonical IL-13, IL-5, and amphiregulin cytokines expression. Upon damage, necrotic epithelial cells can release IL-33 while apoptotic epithelial cells, can release ATP, that further activates mast cells to release IL-33. Alternatively, epithelial cells can release TSLP or the newly identified and specialized chemosensory epithelial cells, namely tuft cells, can release IL-25. Recently mucosal sensory nervous system has been shown to detect helminths and protists and release in response Neuromedin (Nmu) or vasoactive intestinal polypeptide (VIP) that can both activates by themselves ILC2s or synergise with alarmins to potentiate ILC2 response. Finally, some cytokines and lipid mediators have emerged as potential controllers of ILC2s, with the prostaglandin PGI2 and the lipoxin LXA4 limiting ILC2 cytokines release, while the prostaglandin PGD2 and the leukotriene LTD4 can potentiate the same cytokine expression. The regulatory IL-27 cytokines as well as Interferon (IFN)g can dampen ILC2 activation.