The immunology field recently witnessed an interesting development in the discovery of an extended family of ILCs that seem to play an important role in tissue remodeling and in the defense against microorganisms and helminthic parasites [
56]. ILCs have been described previously, with natural killer (NK) cells and lymphoid tissue inducer (LTi) cells as the best known protagonists [
57,
58]. New members of the ILC family share characteristics of NK cells and LTi cells in that they not only express NK markers such as NKp44 and NKp46, but also LTi markers such as CD127 (IL-7 receptor chain α) and the transcription factor RORγt [
56]. Moreover, these cells are able to produce IL-17 or IL-22 and in this respect resemble some of the different subtypes of Th cells that play such an important role in the different branches of the adaptive immune system. The parallel with the adaptive immune system was further strengthened by the description of an ILC type that is able to produce the archetypal Th2 cytokines IL-5 and IL-13. Given their ability to produce IL-13, these cells have been named
nuocytes (after the 13th letter of the Greek alphabet) or ILC2s (after their resemblance to Th2 cells) [
59,
60]. They were originally described only in mice gut, but we have recently discovered that this cell type is highly enriched in nasal polyps of CRS patients [
61••]. These cells produce IL-5 and IL-13 and respond to exposure to IL-25 and IL-33 produced by several cell types in nasal polyps, including macrophages, mast cells, and epithelial cells. This would tie in with the observation that epithelial cells isolated from nonresponsive polyps (return of visible polyps within 6 months after surgery despite postoperative use of local and oral steroids) showed higher basal mRNA levels of IL-33 than epithelial cells isolated from responsive polyps [
25,
62]. Moreover, reports show that downstream of ILC2s, CRS with NP is associated with lower levels of expression of the epithelial IL-22 receptor compared with healthy individuals or CRS patients without NP [
63], and that polymorphisms in the gene are correlated with disease severity [
27]. Given the ability of nasal epithelial cells to respond to IL-13 and IL-22, such a potential should consider that IL-33 can also be produced by fibroblasts and that IL-33 receptors can also be found on mast cells, eosinophils, and Th2 lymphocytes [
12]. Despite these obvious restrictions, the negative or positive feedback loop may contribute to the severity of the disease or its treatment. However, it is noteworthy that IL-33 mRNA levels are somewhat enhanced by the TLR agonist CpG in epithelial cells from treatment-resistant CRS, but not in epithelial cells from treatment-responsive CRS [
64], which would again link CRS to aberrant antimicrobial immunity. Although the precise role of ILCs in general and ILC2s in particular in immune responses or the pathogenesis of CRS is still unknown, they could offer some explanation for the Th2/eosinophilic-like phenotype of NP without a prerequisite concomitant allergic response. Given the absence of RAG recombinase-dependent rearranged antigen receptors on ILCs, the immune responses mediated by these cells are most likely polyclonal in nature. However, exactly if and how ILC2s influence the evident aberrant adaptive immune responses seen in CRS inflammation remains unclear. Whether the discovery of ILCs heralds the end to the darkness that surrounds the pathogenesis of CRS or just adds another level of complexity surely will be the topic of interesting new lines of research.