Metabolic Control of Innate Lymphoid Cell Migration

Abstract

Innate lymphoid cells (ILCs) are specialized immune cells that rapidly respond to environmental challenges, such as infection and tissue damage. ILCs play an important role in organ homeostasis, tissue repair, and host defense in the mucosal tissues intestine and lung. ILCs are sentinels of healthy tissue function, yet it is poorly understood how ILCs are recruited, strategically positioned, and maintained within tissues. Accordingly, ILC migration is an area that has recently come into focus and it is important to define the signals that control ILC migration to and within tissues. In this context, signals from the local tissue microenvironment are relevant. For example, ILCs in the intestine are exposed to an environment that is rich in dietary, microbial, and endogenous metabolites. It has been shown that the Vitamin A metabolite retinoic acid promotes ILC1 and ILC3 homing to the intestine. In addition, recent studies have discovered cholesterol metabolites (oxysterols) as a novel class of molecules that regulate ILC migration through the receptor GPR183. ILCs are considered to be largely tissue-resident cells, yet recent data indicate that ILCs actively migrate during inflammation. Furthermore, the discovery of circulating ILC precursors in humans and their presence within tissues has fueled the concept of local ILC-poiesis. However, it is unclear how circulating ILCs enter tissue during embryogenesis and inflammation and how they are directed to local tissue niches. In this review, I will discuss the metabolic signals that regulate ILC homing and their strategic positioning in healthy and inflamed tissues. It is becoming increasingly clear that ILC function is closely linked to their tissue localization. Therefore, understanding the tissue signals that control ILC migration could open new avenues for the treatment of chronic inflammatory diseases and cancer.

Keywords: cancer; inflammation; innate lymphoid cells; metabolism; migration; oxysterol.

Figure 1

Tissue homing and positioning of ILCPs and mature ILCs. ILCPs derived from fetal (liver) or adult (bone marrow) hematopoiesis enter the blood to home to lymphoid and non-lymphoid organs. This process requires CXCR16 and α4β7 integrin, which bind to CXCL16 and MAdCAM-1, respectively. NK cells egress from the bone marrow is mediated by S1PR5-S1P. Recent data support the concept that circulating ILCPs are a source of local ILC-poiesis after their migration into tissues. ILCPs and ILC1s recirculate between lymph nodes and blood through the use of CD62L, CCR7, and S1P receptors. During embryogenesis, LTi cells are essential for lymph node (LN) formation, which is initiated by their CXCR5-CXCL13-dependent clustering at lymph node anlagen. CCR6-CCL20 positions ILC3s to hair follicles and recruits ILC3s during skin inflammation. In the liver, CXCR6 and its ligand CXCL16 are essential for NK cell memory responses. ILC2s promote thermogenesis, but the signals regulating their migration in adipose tissue are unknown.

Figure 2

ILC trafficking and positioning in the intestine. ILC homing to the small intestine is mediated by α4β7 integrin and the chemokine receptor CCR9 and their respective ligands MAdCAM-1 and CCL25. ILC2s in the bone marrow already express CCR9 and are therefore capable of homing to the small intestine directly. In contrast, retinoic acid is required to induce CCR9 expression in ILC1s and ILC3s after their CCR7-dependent trafficking to mesenteric lymph nodes (mLN). After homing to the intestine, ILC3s are positioned within different tissue niches by distinct signals: (i) CCR6⁺ LTi-like ILC3s localize to cryptopatches (CP) and isolated lymphoid follicles (ILF) through the GPR183-mediated sensing of 7α,25-dihydroxycholesterol (7α,25-OHC). CP/ILF-resident ILC3s stimulate IgA production by interacting with B cells and support crypt stem cells through the constitutive production of IL-22. (ii) NKp46⁺ ILC3s are positioned to intestinal villi through CXCR6-CXCL16, which promotes host defense against intestinal pathogens via IL-22. (iii) Microbiota-produced butyrate regulates the regional residence of NKp46⁺ ILC3s in Peyer's Patches (PP), which controls intestinal tolerance through GM-CSF secretion and regulatory T cells (Treg). (iv) GPR183 and its ligand 7α,25-OHC are also essential for the localization of CCR6⁺ LTi-like ILC3s to the interfollicular region within mLNs, where they interact with T follicular helper cells (TFH) and B cells to regulate IgA production.

Figure 3

ILC migration in the lung. Suppression of CXCR4 by IL-33 enables ILC2Ps to egress from the bone marrow and home to the lung, where they occupy a perivascular niche. This strategic localization likely allows ILC2-mediated recruitment of eosinophils from the circulation into the lung. In addition, prostaglandin D2 stimulates ILC2 migration in the lung through the interaction with its receptor CRTH2 on ILC2s. ILC2s thereby promote type 2 barrier immunity, but also allergic inflammation as in asthma. During helminth infection, IL-25-responsive inflammatory ILC2s (iILC2s) are capable of trafficking from the intestine to the lung, where they support anti-helminth immunity. This inter-organ trafficking requires S1PR1-S1P. LTi-like ILC3s migrate in the lung using CXCR5-CXCL13 and likely neuropilin-1-VEGF-A. LTi-like ILC3s mediate the formation of inducible bronchus-associated lymphoid tissue (iBALT), which is essential for the early control of tuberculosis (TB) in the lung, but may also be involved in inflammatory responses occurring in chronic obstructive pulmonary disease (COPD).

Figure 4

The GPR183-oxysterol pathway positions ILC3s in the colon. In steady-state, LTi-like ILC3s are recruited to cryptopatches by the receptor GPR183 that senses locally produced cholesterol metabolites (oxysterols). The GPR183 ligand 7α,25-dihydroxycholesterol (7α,25-OHC) is produced by CD34⁺ fibroblastic stromal cells. The interaction of GPR183⁺ LTi-like ILC3s with stromal cells leads to cryptopatch formation in steady-state. Inflammation increases 7α,25-OHC production and promotes the migration of GPR183⁺ ILC3s and myeloid cells to inflammatory foci within the colon. Adapted from reference (21).