Trends in Immunology
ReviewMigration and Tissue Tropism of Innate Lymphoid Cells
Introduction
ILCs emerge from the lymphoid lineage and are characterized by the lack of expression of lymphocyte antigen receptors. ILCs have been divided into three different subsets – ILC1, ILC2, and ILC3 – according to their dependence on distinct lineage-determining transcription factors (reviewed in 1, 2, 3). This classification scheme includes phenotypically and functionally distinct cells in common subsets; for example, the ILC3 subset includes both CCR6− (chemokine CC motif receptor) NKp46+/− (natural killer cell P46-related protein/NCR1) ILC3, and CCR6+ CD4+/− lymphoid tissue inducer (LTi) subsets 4, 5. It is clear that much remains to be understood with regard to how development of ILCs relates to their function in the periphery.
In terms of effector function, ILCs exhibit striking similarities to T cells. Similarly to CD8+ T cells, natural killer (NK) cells are cytotoxic to tumor cells and virus-infected cells. Signature cytokines of type 1 T helper (Th1), Th2, and Th17 cells are produced by ILC1, ILC2, and ILC3 cells, respectively. ILC1 produce interferon (IFN)-γ and tumor necrosis factor (TNF)-α; ILC2 produce interleukins (IL)-4, IL-5, IL-9, IL-13 and amphiregulin; and ILC3 produce LTα1β2, IL-17A, IL-22, granulocyte macrophage colony-stimulating factor (GM-CSF), and TNFα 1, 2, 3. ILCs use these cytokines to fight infection by intracellular pathogens (ILC1), helminths (ILC2), and extracellular pathogens (ILC3). ILC1 and ILC3 have been associated with inflammatory disease, and ILC2 play central roles in Th2 type allergic inflammation and in the regulation of metabolic homeostasis 6, 7, 8, 9, 10, 11, 12. T cell effector function is associated with migration to target tissues, which is preceded by migration of naïve T cells from the thymus to secondary lymphoid tissues (SLTs) 13, 14, 15. Similarly, effector function of mature myeloid cells requires migration from the bone marrow, as either precursors or mature cells, to peripheral tissues [16]. ILC subsets have differential tissue distribution, as discussed further below, and the factors that determine this tissue-specific migration and residence, as well as the trafficking mechanisms involved, are an area of active investigation. In particular, given that ILCs have characteristics of both innate and adaptive immune cells, how do ILC migration programs relate to those of other immune cell subsets?
ILCs are widely distributed throughout barrier and non-barrier tissues including the skin, intestines, lungs, uterus, liver, spleen, and SLTs, and tissue localization is strongly associated to subset type 17, 18, 19, 20, 21. Recent studies have revealed that some ILCs, specifically ILC1 and ILC3, express lymphoid tissue-homing receptors (HRs) to migrate into SLTs, and can switch expression of HRs to migrate to non-lymphoid tissues in a manner similar to T cells 22, 23. ILC2, on the other hand, appear to migrate directly from the hematopoietic site to target tissues, in a manner similar to myeloid cells and some innate T cells [22]. Trafficking receptors play important roles in ILC tissue tropism and interaction with other cell types 22, 24, 25, and recent evidence suggests that they may be important for the migration of bone marrow ILC progenitors to peripheral tissues [26]. Furthermore, specific tissue tropism of ILCs is important for their functions in immune regulation 22, 23, 24, 25, 27.
We review here current understanding of the migration programs that mediate the distribution of ILC subsets in different tissues. We begin by integrating evidence for differential tissue distribution of ILC subsets in both mice and human, and compare it, when relevant, to our understanding of T cells and innate immune cell migration programs. In this context, we outline common and distinct features of the migration programs of ILC subsets, discuss how they relate to ILC development and function, and outline areas requiring further investigation in this rapidly moving field.
Section snippets
Tissue Distribution of ILC Subsets
ILCs are widely distributed in the body, and a growing body of evidence suggests that ILC subsets are strategically localized in specific tissues in a manner that relates to their roles in immune and inflammatory responses 10, 11, 28, 29, 30, 31, 32, 33, 34, 35, 36. Most studies to date focus on one or two ILC subsets and tissue types; to present a more comprehensive view we have integrated available data on ILC tissue distributions (Figure 1). NK cells are the dominant population in the bone
Origins of Peripheral ILCs
ILCs emerge from fetal progenitors and adult bone-marrow progenitors 39, 40. ILCs populate various tissues from mid to late stages of fetal development. In mice, fetal ILC progenitors with an LTi phenotype populate the intestine as early as embryonic day (E)12.5–13.5, and develop lymphoid structures such as PPs via the expression of LTα1β2 41, 42. These progenitors also have the potential to become ILC1 and ILC2 in the gut. T-bet+ (T box 21/TBX21), RORγt+ [retinoic acid receptor (RAR)-related
Homing Receptors for ILCPs
HRs, including integrins and chemoattractant receptors, regulate the migration of hematopoietic progenitors and mature cells 55, 56. The NK/ILC progenitors, αLP, express the integrin α4β7 and the chemokine receptor CXCR6 52, 53. ILCPs also express α4β7 [39]. These receptors are implicated in immune cell migration and cell–cell interaction in peripheral tissues. MAdCAM-1 (mucosal vascular addressin cell adhesion molecule 1), the major binding partner for α4β7, is highly expressed by the
Tissue factors for Differentiation and Population of ILCs in Peripheral Tissues
In general, the factors that induce the differentiation, expansion and contraction of ILCs have the potential to control ILC tissue distribution. Cytokines induce the proliferation and differentiation of ILCPs. IL-7 is widely expressed in the body and supports the generation of all ILCs, including non-NK ILCs and NK cells 36, 70, 71, 72. NK cell development from αLP is induced by IL-15 73, 74, 75. IL-7 is also required for the generation of T and B cells, and IL-15 is also required for the
Migration of Mature ILCs to Lymphoid Tissues
While the majority of ILCs in SLTs are NK cells, non-NK ILCs such as ILC1, ILC2, and ILC3 are also present in SLTs at detectable levels (Figure 1). The ILCs in SLTs have the potential to influence the activation and differentiation of T and B cells 80, 94. In addition, SLTs would provide a conducive environment for functional maturation of ILCs themselves through ILC-activating signals from dendritic cells. Mature ILCs in SLTs can be generated in situ from ILC progenitors or mature ILCs that
Trafficking Receptor Switches and the Establishment of ILC Tissue Residency in Non-Lymphoid Tissues
Naïve T cells acquire non-lymphoid tissue HRs while they undergo differentiation in SLTs. For example, naïve T cells acquire CCR9 and α4β7 expression in MLNs or PPs to migrate to the gut [103]. However, they acquire skin HRs such as cutaneous lymphocyte antigen (CLA), CCR4, CCR8, and CCR10 in skin-draining lymph nodes [104]. CCR4, CCR8, and CCR10 are implicated in lymphocyte trafficking to inflamed skin tissues 105, 106, 107, 108. This process is termed the ‘HR or trafficking receptor switch’ (
Concluding Remarks
The migration programs of ILCs have been unclear, but recent progress has revealed new insights into migration potential and tissue tropism. First, ILC progenitors or precursors in the bone marrow and fetal liver migrate to the periphery for development and maturation. ILCPs express α4β7, CCR7, CCR9, and/or CXCR6 for migration to barrier and non-barrier tissues, such as spleen, liver, lymph nodes, skin, and mucosal tissues. The migration of ILC progenitors or precursors to peripheral tissues
Acknowledgments
This work was supported, in part, from grants from the National Institutes of Health (R01AI0 74745, R01DK0 76616, 1S10RR 02829, and R01AI0 80769) and the National Multiple Sclerosis Society to C.H.K. The authors thank L. Friesen at Purdue University for critical reading of the manuscript.
References (122)
Innate lymphoid cells in inflammation and immunity
Immunity
(2014)Interleukin-33 and interferon-gamma counter-regulate group 2 innate lymphoid cell activation during immune perturbation
Immunity
(2015)Activated type 2 innate lymphoid cells regulate beige fat biogenesis
Cell
(2015)T-cell recruitment to the intestinal mucosa
Trends Immunol.
(2008)Migration and function of FoxP3+ regulatory T cells in the hematolymphoid system
Exp. Hematol.
(2006)Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells
Immunity
(2013)Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut
Immunity
(2015)The chemokine receptor CXCR6 controls the functional topography of interleukin-22 producing intestinal innate lymphoid cells
Immunity
(2014)CXCL13 expression in the gut promotes accumulation of IL-22-producing lymphoid tissue-inducer cells, and formation of isolated lymphoid follicles
Mucosal Immunol.
(2009)Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production
Immunity
(2004)
Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients
J. Invest. Dermatol.
Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages
Cell
Emergence of NK-cell progenitors and functionally competent NK-cell lineage subsets in the early mouse embryo
Blood
The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells
Immunity
Human RORgammat+CD34+ cells are lineage-specified progenitors of group 3 RORgammat+ innate lymphoid cells
Immunity
T-bet and Gata3 in controlling type 1 and type 2 immunity mediated by innate lymphoid cells
Curr. Opin. Immunol.
How do stem cells find their way home?
Blood
Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes
Cell
CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus
Blood
A key role for CCR7 in establishing central and peripheral tolerance
Trends Immunol.
Expression and function of interleukin-7 in secondary and tertiary lymphoid organs
Semin. Immunol.
Multifaceted roles of interleukin-7 signaling for the development and function of innate lymphoid cells
Semin. Immunol.
IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation
Immunity
Innate lymphoid cells: balancing immunity, inflammation, and tissue repair in the intestine
Cell Host Microbe
Retinoic acid, immunity, and inflammation
Vitam. Horm.
The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells
Immunity
Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense
Immunity
Transcriptional regulation of innate lymphoid cell fate
Nat. Rev. Immunol.
Innate lymphoid cells in the initiation, regulation and resolution of inflammation
Nat. Med.
The biology of innate lymphoid cells
Nature
Group 3 innate lymphoid cells (ILC3s): origin, differentiation, and plasticity in humans and mice
Eur. J. Immunol
A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis
J. Exp. Med.
Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages
J. Exp. Med.
Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice
J. Immunol
Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity
Nature
The unusual suspects – innate lymphoid cells as novel therapeutic targets in IBD
Nat. Rev. Gastroenterol. Hepatol.
Chemokines in the systemic organization of immunity
Immunol. Rev.
Development of monocytes, macrophages, and dendritic cells
Science
Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets
Nat. Immunol.
Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues
Nat. Immunol.
Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity
Science
Immature NK cells, capable of producing IL-22, are present in human uterine mucosa
J. Immunol.
CCR7-dependent trafficking of RORgamma+ ILCs creates a unique microenvironment within mucosal draining lymph nodes
Nat. Commun.
Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses
Nat. Immunol.
CXCR6 expression is important for retention and circulation of ILC precursors
Mediators Inflamm.
Type 2 innate lymphoid cells control eosinophil homeostasis
Nature
Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity
Nat. Med.
Essential, dose-dependent role for the transcription factor Gata3 in the development of IL-5+ and IL-13+ type 2 innate lymphoid cells
Proc. Natl. Acad. Sci. U.S.A.
New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25
J. Immunol.
Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin
Nat. Immunol.
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