Innate Lymphoid Cells in Response to Intracellular Pathogens: Protection Versus Immunopathology

Abstract

Innate lymphoid cells (ILCs) are a heterogeneous group of cytokine-producing lymphocytes which are predominantly located at mucosal barrier surfaces, such as skin, lungs, and gastrointestinal tract. ILCs contribute to tissue homeostasis, regulate microbiota-derived signals, and protect against mucosal pathogens. ILCs are classified into five major groups by their developmental origin and distinct cytokine production. A recently emerged intriguing feature of ILCs is their ability to alter their phenotype and function in response to changing local environmental cues such as pathogen invasion. Once the pathogen crosses host barriers, ILCs quickly activate cytokine production to limit the spread of the pathogen. However, the dysregulated ILC responses can lead to tissue inflammation and damage. Furthermore, the interplay between ILCs and other immune cell types shapes the outcome of the immune response. Recent studies highlighted the important role of ILCs for host defense against intracellular pathogens. Here, we review recent advances in understanding the mechanisms controlling protective and pathogenic ILC responses to intracellular pathogens. This knowledge can help develop new ILC-targeted strategies to control infectious diseases and immunopathology.

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

“…These results, only revealed through RORγt-Cre fate mapping strategies, highlight the plasticity of intestinal RORγt + ILC3 subsets and their ability to switch from “homeostatic” ILC3s to IFNγ-producing “inflammatory” ex-ILC3s/ILC1s. While the transition of NCR + ILC3s to ex-ILC3s/ILC1s can be pathogenic, this plasticity is dichotomous and may also be beneficial by evoking protective immunity to certain intracellular pathogens through the production of pro-inflammatory cytokines, namely IFNγ that enables the production of mucus-forming glycoproteins to protect the epithelial barrier ( 53 , 93 ).…”

Innate Lymphoid Cell Plasticity in Mucosal Infections

“…Innate lymphoid cells (ILCs) are an essential part of innate mucosal immunity. ILCs can sense environmental changes and rapidly respond by producing effector cytokines to limit pathogens spread, initiate tissue recovery, regulate epithelial cell differentiation and activate other immune cells, thereby facilitating inflammatory response [ 3 , 4 , 5 ]. Moreover, recent studies reported that ILCs can regulate the activity of adaptive immune cells through direct cell-to-cell contact and cytokine production [ 3 , 6 , 7 , 8 , 9 , 10 ].…”

“…Thus, the transcription factor Eomes controls NK cells differentiation, while T-bet, GATA3 and RORγt are important for ILC1, ILC2 and ILC3 development and their effector cytokine production, respectively [ 13 , 16 ]. Intracellular pathogens and viruses activate ILC1s to produce IFNγ and TNF [ 5 , 17 ]. Along with these effector cytokines, NK cells can mediate cytotoxic activity by releasing perforins and granzymes to induce apoptosis of target cells [ 18 , 19 ].…”

“…ILC3→ILC1 plasticity is driven by IL-12 and IL-1β, leading to downregulation of RORγt and upregulation of T-bet [ 12 , 29 , 35 , 36 ]. T-bet is critical for IFNγ production, which is necessary for protection against intracellular pathogens [ 5 , 17 ]. Conversely, ILC1→ILC3 plasticity is driven by IL-23, IL-1β, and retinoic acid (RA), which leads to upregulation of RORγt and downregulation of T-bet [ 29 ].…”

“…Accumulating evidence suggests that ILC transdifferentiation can be reversed, underlying the existence of mechanisms balancing ILC composition under physiological conditions and pathogen invasion to prevent excessive inflammation. It is now evident that ILC plasticity is not only an important driver of protective immune responses but can also lead to exacerbation of various chronic and inflammatory diseases [ 5 , 12 , 42 , 46 , 47 ]. However, the molecular mechanisms of ILC plasticity and its impact on immune response to mucosal pathogens remain poorly understood.…”