Innate lymphoid cells: More than just immune cells

Abstract

Since their discovery, innate lymphoid cells (ILCs) have been described as the innate counterpart of the T cells. Indeed, ILCs and T cells share many features including their common progenitors, transcriptional regulation, and effector cytokine secretion. Several studies have shown complementary and redundant roles for ILCs and T cells, leaving open questions regarding why these cells would have been evolutionarily conserved. It has become apparent in the last decade that ILCs, and rare immune cells more generally, that reside in non-lymphoid tissue have non-canonical functions for immune cells that contribute to tissue homeostasis and function. Viewed through this lens, ILCs would not be just the innate counterpart of T cells, but instead act as a link between sensory cells that monitor any changes in the environment that are not necessarily pathogenic and instruct effector cells that act to maintain body homeostasis. As these non-canonical functions of immune cells are operating in absence of pathogenic signals, it opens great avenues of research for immunologists that they now need to identify the physiological cues that regulate these cells and how the process confers a finer level of control and a greater flexibility that enables the organism to adapt to changing environmental conditions. In the review, we highlight how ILCs participate in the physiologic function of the tissue in which they reside and how physiological cues, in particular neural inputs control their homeostatic activity.

Keywords: IL-22; ILC1; ILC2; ILC3; gut homeostasis; metabolic homeostasis; neuroimmune interaction; physiological sensors.

Figure 1

ILCs in the adipose tissue. ILC1s and ILC2s regulate the balance between M1 and M2 macrophages in the adipose tissue. External stimuli such as high-fat diet (HFD) or cold exposure modulate the activity of the ILC which impacts the M1/M2 ratio in the tissue. ILC1 promotes M1 macrophage polarization through the production of TNF-α and IFN-γ, which increases not only lipid storage but also inflammation and adipose fibrosis. ILC2s are activated by IL-33 and regulated by the sympathetic nervous system (SNS) in response to cold exposure. Consequently, IL-5 and IL-13 production by ILC2s is enhanced, which promotes eosinophil recruitment and M2 macrophage polarization, respectively. This type 2 response promotes the beiging of adipose tissues and thermogenesis.

Figure 2

ILC2 in the in lungs. ILC2 activity is rapidly induced by the first breath which promotes IL-33 secretion in the lungs. IL-33 acts on ILC2s to induce their production of both IL-5 and IL-13 that regulate the homeostasis of eosinophils and M2 macrophages. IL-33 also promotes ILC2 activity through the secretion of calcitonin gene‐related peptide (CGRP) produced by pulmonary neuroendocrine cells (PNECs). IL-5 derived from ILC2s, which are stimulated by VIP, further promotes vasoactive intestinal peptide (VIP) production by pulmonary c-fibers, creating a positive feedback loop. The parasympathetic nervous system (PNS) and SNS mainly act as negative feedback loop in response to inflammatory signals and prevent tissue damage.

Figure 3

Neuro-ILCs interaction in intestinal tract and peritoneal tissue. Intense communications between ILCs and nerves have been described in the gut. Constitutive expression of IL-25 by Tuft cells regulates ILC2 numbers and IL-13 expression. IL-13 in turn fosters Tuft cell differentiation and induces mucus production by goblet cells. Activation of ILC2s by IL-25 is inhibited by CGRP produced by ChAT⁺ enteric neurons. These neurons can also express NMU which activates ILC2s during inflammation. ILC3s are the main producers of IL-22 at steady state which regulates the anti-microbial production by Paneth cells and the proliferation of intestinal stem cells. Heparin-binding epidermal growth factor–like growth factor (HB-EGF) produced by ILC3 protects intestinal epithelial cells from TNF-induced cell death. IL-22 production is enhanced by enteric nervous system (ENS)-derived VIP in response to cholecystokinin (CCK) secreted by enteroendocrine cells that are activated by food intake. ILC3s also respond to glial-derived neurotrophic factor (GDNF) produced by enteric glial cells. Peritoneal ILC3s are regulated by the PNS through the neurotransmitter acetylcholine (ACh). Specifically, ACh promotes the production of protectin conjugates in tissue regeneration 1 (PCTR1) by peritoneal ILC3s, enhancing tissue resolution after inflammation.