Localization and site-specific cell–cell interactions of group 2 innate lymphoid cells

Group 2 innate lymphoid cells (ILC2s) are novel lymphocytes discovered in 2010. Unlike T or B cells, ILC2s are activated non-specifically by environmental factors and produce various cytokines, thus playing a role in tissue homeostasis, diseases including allergic diseases, and parasite elimination. ILC2s were first reported as cells abundantly present in fat-associated lymphoid clusters in adipose tissue. However, subsequent studies revealed their presence in various tissues throughout the body, acting as key players in tissue-specific diseases. Recent histologic analyses revealed that ILC2s are concentrated in specific regions in tissues, such as the lamina propria and perivascular regions, with their function being controlled by the surrounding cells, such as epithelial cells and other immune cells, via cytokine and lipid production or by cell–cell interactions through surface molecules. Especially, some stromal cells have been identified as the niche cells for ILC2s, both in the steady state and under inflammatory conditions, through the production of IL-33 or extracellular matrix factors. Additionally, peripheral neurons reportedly co-localize with ILC2s and alter their function directly through neurotransmitters. These findings suggest that the different localizations or different cell–cell interactions might affect the function of ILC2s. Furthermore, generally, ILC2s are thought to be tissue-resident cells; however, they occasionally migrate to other tissues and perform a new role; this supports the importance of the microenvironment for their function. We summarize here the current understanding of how the microenvironment controls ILC2 localization and function with the aim of promoting the development of novel diagnostic and therapeutic methods.