“Just one word, plastic!”: Controversies and caveats in innate lymphoid cell plasticity

Abstract

Innate lymphoid cells (ILCs) are frontline immune effectors involved in the early stages of host defense and maintenance of tissue homeostasis, particularly at mucosal surfaces such as the intestine, lung, and skin. Canonical ILCs are described as tissue-resident cells that populate peripheral tissues early in life and respond appropriately based on environmental exposure and their anatomical niche and tissue microenvironment. Intriguingly, there are accumulating reports of ILC “plasticity” that note the existence of non-canonical ILCs that exhibit distinct patterns of master transcription factor expression and cytokine production profiles in response to tissue inflammation. Yet this concept of ILC-plasticity is controversial due to several confounding caveats that include, among others, the independent large-scale recruitment of new ILC subsets from distal sites and the local, in situ, differentiation of uncommitted resident precursors. Nevertheless, the ability of ILCs to acquire unique characteristics and adapt to local environmental cues is an attractive paradigm because it would enable the rapid adaptation of innate responses to a wider array of pathogens even in the absence of pre-existing ‘prototypical’ ILC responder subsets. Despite the impressive recent progress in understanding ILC biology, the true contribution of ILC plasticity to tissue homeostasis and disease and how it is regulated remains obscure. Here, we detail current methodologies used to study ILC plasticity in mice and review the mechanisms that drive and regulate functional ILC plasticity in response to polarizing signals in their microenvironment and different cytokine milieus. Finally, we discuss the physiological relevance of ILC plasticity and its implications for potential therapeutics and treatments.

Single-cell RNA sequencing of cerebrospinal fluid reveals the expansion of innate lymphoid cells with upregulated transposable elements in multiple sclerosis

“…We nd out that ILCs that are expanded in MS revealed a distinct pattern for TE upregulation. The upregulation of TEs in these cells is in accordance with the adaptive phenotype and functional capacities of these cells in response to stimuli (29,50). One may speculate that the genomic plasticity of ILCs could be obtained by inserting of TEs in coding or regulatory regions of immune-related genes, functional impact on the gene regulation, and the resultant plasticity (31).…”

Epithelial–immune cell interactions in allergic diseases

“…Intraepithelial lymphocytes are significantly involved in the homeostatic maintenance of the epithelial barrier, especially in the GI tract, where they represent one of the largest lymphocyte populations of the body, but also in other epithelial tissues [43,51,52]. While B cells are rather rare, intraepithelial lymphocytes mainly comprise different types of innate lymphoid cells, which do not have antigen-specific receptors and T cells [53]. Interestingly, the latter consist not only of conventional αβ TCR T cells, including tissue-resident memory T cells [54], but also of a variety of different unconventional T cell subsets such as γδ TCR-bearing including dendritic epithelial T cells [55,56], CD8αα [55], and CD4CD8αα T cells [57].…”

Perinatal brain group 3 innate lymphoid cells are involved in the formation of murine dural lymphatics

“…Additionally, plasticity events mediated by e.g. tissue-derived cytokines have been reported within all ILC subsets 17,18 , leading to the generation of a plethora . CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

“…Additionally, plasticity events mediated by e.g. tissue-derived cytokines have been reported within all ILC subsets 17,18 , leading to the generation of a plethora of intermediate populations [19][20][21][22] . Overall, these processes of layered ontogeny, adult-derived turnover, and ILC plasticity, facilitate the adaptation of tissue-specific ILCs to external stimuli during immune activation and physiological processes of tissue development, homeostasis and aging 12,23,24 .…”