International Immunology International Immunology Advance Access published May 12, 2014
Regulation of intestinal health and disease by Innate lymphoid cells
International Immunology
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Manuscript ID: Manuscript Type: Date Submitted by the Author:
Keywords:
Invited Review
02-May-2014
Sonnenberg, Gregory; University of Pennsylvania,
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Complete List of Authors:
INTIMM-14-0065.R1
mucosal immunology, inflammatory bowel disease, intestinal homeostasis, innate lymphoid cells
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Journal:
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International Immunology
Regulation of intestinal health and disease by Innate lymphoid cells
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Gregory F. Sonnenberg
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Division of Gastroenterology, Department of Medicine, and Institute for Immunology, Perelman School of
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Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
7 CORRESPONDENCE Gregory F. Sonnenberg, [email protected]
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Running title: Intestinal innate lymphoid cells
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Keywords: Intestinal homeostasis, mucosal immunology, inflammatory bowel disease, innate lymphoid
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Abstract
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Innate lymphoid cells (ILCs) are a recently appreciated immune cell population that is constitutively found
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in the healthy mammalian gastrointestinal (GI) tract and associated lymphoid tissues.
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studies have revealed that alterations in ILC populations are associated with GI disease in patients, such
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as inflammatory bowel disease (IBD), HIV infection and colon cancer, suggesting a potential role for ILCs
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in either maintaining intestinal health or promoting intestinal disease. Mouse models identified that ILCs
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have context-dependent protective and pathologic functions either during the steady state, or following
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infection, inflammation or tissue damage. This review will discuss the associations of altered intestinal
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ILCs with human GI diseases, and the functional consequences of targeting ILCs in mouse models.
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Collectively, our current understanding of ILCs suggests that the development of novel therapeutic
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strategies to modulate ILC responses will be of significant clinical value to prevent or treat human GI
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diseases.
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Innate lymphoid cells (ILCs) are a family of innate immune cells that critically contribute to the state of
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health or disease in the mammalian gastrointestinal (GI) tract. The development, heterogeneity, plasticity
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and regulation of ILCs have been extensively reviewed elsewhere (1-7). In brief, ILCs develop from
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lymphoid precursors in a process regulated by the common γ-chain cytokine receptor and the transcription
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factors Id2, TCF1 and GATA3. Mature ILCs express the IL-7 receptor (CD127), but lack surface markers
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associated with other immune cell lineages, including T cells, B cells, granulocytes and myeloid cells.
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Further, ILCs can be divided into three groups based on transcriptional regulation. Group 1 ILCs (ILC1)
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constitutively express T-bet but not RORγt, group 2 ILCs (ILC2) constitutively express GATA3 but not
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RORγt, and group 3 ILCs (ILC3) constitutively express RORγt. There are numerous shared regulatory and effector pathways that are associated with each group
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of ILCs. For example, ILC1 respond to IL-12 and IL-18 to produce IFN-γ and TNF-α, ILC2 respond to IL-
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25, IL-33 and TSLP to produce IL-5, IL-9, IL-13 and amphiregulin, and ILC3 respond to IL-1β and IL-23 to
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produce IL-17 and IL-22.
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populations. Currently, ILC1 encompass classical NK cells (which will not be discussed in this review) and
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recently identified ILC1 that lacks expression of eomesodermin and cytolytic potential, and can be
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heterogeneous in expression of natural cytotoxicity receptors (NCRs), such as NKp46 and NKp44. ILC3
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encompass CCR6 cells that most closely resemble fetal lymphoid tissue inducer (LTi) cells and CCR6
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cells that can co-express T-bet and NCRs.
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heterogeneity in groups of ILCs remain unclear and are active areas of investigation.
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However, significant heterogeneity has been found in ILC1 and ILC3
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The lineage relationships, plasticity and significance of
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Analyses of ILCs in humans and mice have revealed that the GI tract and associated lymphoid
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tissues constitutively contain populations of ILCs under homeostatic conditions. Further, studies in patient
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populations with diseases that affect the GI tract, including inflammatory bowel disease (IBD), HIV and
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cancer, have revealed significant alterations in either the composition or the functional potential of ILC
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populations. Mouse models have identified several critical pathways by which ILCs can directly modulate
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intestinal homeostasis, immunity, inflammation and tissue repair, suggesting that further interrogation of
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ILCs could provoke the development of novel preventative and therapeutic strategies for GI diseases. The
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focus of this review will be to discuss data supporting the idea that that alterations in ILC populations occur
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Introduction
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in the intestine of healthy versus diseased humans, and to highlight functional studies in mice identifying
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context-dependent protective and pathologic roles for intestinal ILCs.
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Human innate lymphoid cells in gastrointestinal health and disease
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Subsets of ILCs were first discovered in the intestinal tract and associated lymphoid tissues of fetal and
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adult donors.
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identified—in the tonsils, Peyer’s patches and lamina propria of adult donors—that constitutively
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expressed NKp44, RORC (which encodes RORγ isoforms) and IL-22 (8). Similarly, a report by Cupedo
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and Spits identified a population of NCR CD127 innate immune cells present in the fetal intestine and
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mesenteric lymph nodes that expressed IL-17 and IL-22, and further characterized a post-natal
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development of NKp44 CD127 cells that express IL-22 and RORC in human tonsils (9). Subsequent
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studies suggested that IL-22-expressing NKp44 cells might be a subset of immature NK cells (10), and
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highlighted many questions regarding the developmental and lineage relationships of innate IL-22- and IL-
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17-expressing cell types in the GI tract and associated lymphoid tissues of humans.
In a seminal study by Colonna and colleagues, a subset of innate immune cells was
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Since those initial reports, more recent studies have demonstrated that these cells are indeed a
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novel innate immune cell population, now termed ILC3, that are distinct from classical NK cells (11) and
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uniquely regulated by environmental and inflammatory stimuli (12-15).
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produce IL-22 and IL-17, two cytokines that induce expression of anti-microbial peptides and inflammatory
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mediators (16), provoked the hypothesis that they were critical regulators of intestinal immunity and
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inflammation.
The ability of ILC3 to rapidly
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Consistent with this, ILC3 were found to be the dominant source of IL-22 in the intestine and
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associated lymphoid tissue of healthy human donors (17) and, as discussed below, alterations in ILC3
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populations were identified in multiple infectious, inflammatory and metabolic diseases affecting the GI
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tract. For example, it was reported by multiple groups that IL-22- and IL-17-expressing ILC3 are depleted
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from the GI tract of non-human primates following infection with a highly pathogenic strain of simian
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immunodeficiency virus (SIV) and induction of tissue damage in the intestine (18-20), a pathway critically
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linked to the progression of AIDS. Further, the presence of IL-22-producing ILC3 populations has been
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correlated with preserved integrity of the GI tract of HIV-infected individuals (21,22), suggesting a
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beneficial role for ILC3 and IL-22 in maintaining intestinal health during chronic viral infection.
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IBD patients have also been reported to exhibit significant alterations in intestinal ILCs. IL-22-
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producing NKp44 ILC3 were found to be reduced in patients with Crohn’s disease (23,24); however,
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these ILC3 were preserved in ankylosing spondylitis patients exhibiting subclinical intestinal inflammation
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(25), suggesting that this population of cells may play a role in limiting the development of clinical GI
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disease. This loss of a potentially ‘protective’ ILC3 population in IBD was also associated with an increase
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in potentially ‘pathologic’ ILCs (23,24,26). Powrie and colleagues identified an expansion of CD127 IL-
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23-responsive, IL-17-producing ILC3 in the intestinal lamina propria of Crohn’s disease patients (26). In a
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seminal study by Spits and colleagues, a subset of IFN-γ-producing ILC1 were found to be increased in
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Crohn’s disease patients relative to non-inflamed controls, and further expansion of human ILC1 could be
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driven by experimental intestinal damage in a humanized mouse model (24). Colonna and colleagues
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also identified a population of T-bet IFN-γ-producing ILC1 residing in the intra-epithelial cell compartment,
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which accumulated in Crohn’s disease patients (27). Collectively, these reports suggest that there are
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significant alterations in the composition or functional potential of intestine-resident ILCs during chronic
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infection or tissue inflammation in humans.
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The mechanisms that result in dysregulated human ILC populations in these chronic diseases
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currently remain unclear.
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pathologic ILCs may occur through altered lineage plasticity or dysregulated exposure to regulatory
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cytokines or microbial stimuli (12-14,24,26,28,29). Further, a recent report identified that IL-22 ILC3 are
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enriched in tumors of patients with colorectal cancer (30), suggesting that alterations in ILCs may be
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present in a broad spectrum of human GI diseases. Finally, although the presence of ILC2 in the intestine
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and associated lymphoid tissues has been identified in non-diseased fetal and adult donors (31), it
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remains poorly defined whether they are dysregulated in the context of intestinal diseases. However, one
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recent report identified an accumulation of IL-13-producing cells that resemble ILC2 in fibrotic Crohn’s
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disease patients (32), suggesting an involvement in pathologic collagen deposition. In future analyses of
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ILCs in the human intestine, it will be important to undertake extensive phenotypic and functional
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characterization to fully elucidate groups of ILCs in the healthy intestine and alterations that may occur in
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infectious, inflammatory or metabolic diseases.
Several studies suggest the loss of protective ILCs and accumulation of
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The role of ILCs in maintaining intestinal health
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Functional studies in mice have revealed that ILCs can play a significant role in maintaining intestinal
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health by promoting immunity to pathogens, limiting inappropriate inflammatory responses to commensal
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bacteria or dietary antigens, or mediating repair following tissue damage. This is accomplished through
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expression of a number of factors that can influence stromal, epithelial, myeloid, granulocyte and adaptive
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immune cell responses (Fig. 1).
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ILCs can be a rapid source of protective cytokines following initial exposure to a variety of pathogens. For
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example, a recently described ILC1 population was found to be an important innate source of IFN-γ and
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TNF-α following oral infection with Toxoplasma gondii, which promoted the recruitment of inflammatory
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monocytes and control of parasite replication (33). ILC2 in the small intestine are critical for promoting
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tissue immunity via rapid production of IL-5 and IL-13, which induces intestinal goblet cell responses and
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expulsion of intestinal nematodes, such as Nippostrongylus brasiliensis (34,35). Finally, ILC3 are a rapid
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source of IL-22 and IL-17, which induce intestinal epithelial cell expression of anti-microbial peptides and
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innate immunity to extracellular bacteria, such as Citrobacter rodentium (8,16,36,37). Therefore, ILCs
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provide rapid cytokine production that is critical to control pathogen replication and clearance early
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following infection.
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As previously reviewed (38), ILCs also play a significant role in modulating adaptive immunity in
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the intestine through either indirect interactions with stromal cells, or direct interactions with adaptive
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immune cells. Studies by Mebius and colleagues identified a subset of ILC3, termed lymphoid tissue
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inducer (LTi) cells, that interacts with stromal cells to induce secondary lymphoid organogenesis prior to
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birth (39,40). Following birth, a complex interplay between mammalian hosts and commensal bacteria
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facilitate the maturation of intestinal cryptopatches to isolate lymphoid follicles by RORγt ILC3 (41,42).
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ILC3 promote the development of GALT through expression of lymphotoxin (LT) and interactions
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with stromal cells, allowing the recruitment of immune cells to discrete organized locations (40). The
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formation of secondary lymphoid tissues in the intestine by ILC3 is critical for orchestrating optimal
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adaptive immunity. For example, regulation of these functions of ILC3 by dietary retinoids significantly
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impacts the magnitude of protective adaptive immune cell responses to mucosal viruses (43). Expression
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of surface-bound LTα1β2 or soluble LTα3 by ILC3 is also essential for generating host-protective IgA in the
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ILCs promote intestinal immunity to pathogens
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GI tract in a T cell-independent and T cell-dependent manner, respectively (44,45). ILC2 have recently
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been described to regulate eosinophil homeostasis in the intestine through constitutive production of IL-5
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(46). While the homeostatic functions of intestinal eosinophils are poorly understood, emerging evidence
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suggests they can contribute to optimal induction of IgA and regulatory T cells (47)
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ILCs can also directly interact with adaptive immune cells to promote tissue immunity.
ILC3 can
promote B cell responses through production of GM-CSF, BAFF and co-stimulatory receptors, and ILC2
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have been shown to be critical regulators of B1 cell proliferation (14,34,48).
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promote maintenance of memory CD4 T cell responses to pathogens through expression of Ox40L and
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CD30L (49). Collectively, ILCs can orchestrate intestinal immunity to pathogens through rapid cytokine-
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ILC3 can also directly
dependent responses, or by facilitating optimal adaptive immune cell responses
ILCs limit inflammatory responses to commensal bacteria and dietary antigens
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A growing body of evidence suggests that ILCs play a critical role in limiting inappropriate immune
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responses to non-harmful environmental stimuli, such as commensal bacteria and dietary antigens. In the
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absence of pathogen infection, loss of ILC3 or IL-22 results in peripheral dissemination of commensal
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bacteria and systemic inflammation (17). Interestingly, disseminating bacteria were found to be of the
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genus Alcaligenes or Achromobacter (17), which were characterized to constitutively colonize the GALT of
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healthy humans, non-human primates and mice (50), suggesting that the ILC3–IL-22 pathway selectively
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regulates the anatomical containment of commensal bacteria in order to limit chronic inflammation.
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Consistent with this, it has been demonstrated that regulation of ILC3 and IL-22 by the aryl
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hydrocarbon receptor (Ahr) is critical to limit colonization of intestinal epithelial cells with segmented
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filamentous bacteria (SFB). Ahr-deficient mice exhibit an overgrowth of SFB and a subsequent increase
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in pro-inflammatory Th17 cells (51). Collectively, these studies suggest that the ILC3–IL-22 pathway is
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critical to maintain intestinal homeostasis by limiting the dissemination and replication of commensal
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bacteria that are intimately associated with mammalian hosts, such as Alcaligenes and Achromobacter
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that are resident in lymphoid tissue, or SFB that are associated with intestinal epithelial cells.
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Emerging evidence suggests that ILC3 may also limit inappropriate immune responses to
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commensal bacteria through other effector pathways. For example, it was recently shown that ILC3 can
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directly limit pro-inflammatory CD4 T cell responses to commensal bacteria through expression of MHC
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class II (MHCII) (52).
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responses to commensal bacteria and spontaneous intestinal inflammation (52). A recent report by Merad
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and colleagues also identified that ILC3 are a dominant source of GM-CSF in the intestine and critically
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regulate myeloid cell homeostasis (53).
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required to maintain optimal Treg cell responses and tolerance to dietary antigens (53). Collectively, these
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results suggest that ILC3 play a central role in regulating intestinal homeostasis by limiting inappropriate
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immune responses to normally beneficial or harmless environmental stimuli.
Loss of ILC-intrinsic MHCII resulted in dysregulated effector CD4 Th17 cell
Intriguingly, ILC3-mediated regulation of myeloid cells was
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ILCs mediate intestinal tissue repair
Production of IL-22 is critical in mediating repair of the intestinal epithelium in the context of tissue damage
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(16). Studies by Eberl and colleagues have highlighted that ILC3 rapidly respond to experimental tissue
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damage in the intestine and mediate IL-22-dependent tissue repair (54). Interestingly, in a mouse model
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of graft versus host disease, ILC3-derived IL-22 maintained intestinal epithelial barrier integrity following
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hematopoietic stem cell transplantation by directly protecting intestinal stem cells from immune-mediated
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damage (55). Acting directly on intestinal stem cells may be one mechanism by which a relatively rare
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population, such as ILC3, can substantially influence homeostasis in the intestine. Collectively, ILCs
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promote multiple beneficial processes in order to maintain a state of health in the mammalian intestine.
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18 The role of ILCs in promoting intestinal disease
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In contrast to the tissue protective roles of intestinal ILCs, dysregulated ILC responses or changes in the
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composition of intestinal ILC populations can promote intestinal inflammation and the development or
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progression of intestinal cancers (Fig. 2).
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Dysregulated ILC responses promote intestinal inflammation
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Pioneering research by Powrie and colleagues (56) identified that IL-23 production in response to
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Helicobacter hepaticus infection, or following dysregulated activation of dendritic cells via anti-CD40
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antibody administration, results in the expansion of a T-bet ILC3 population that promotes colitis in an IL-
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17- and IFN-γ-dependent manner. Later research identified that T-bet co-expression in ILC3 is associated
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with IFN-γ production and enterocolitis following Salmonella infection (57). IL-22 production by ILC3 can
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also promote colitis in some contexts (58), which may be dependent on co-expression of other pro-
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inflammatory cytokines (16).
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promote IFN-γ-dependent intestinal inflammation following anti-CD40 antibody administration (27).
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Emerging evidence suggest that a shift from protective to pathologic ILC responses in the intestine may
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involve lineage plasticity, altered expression of transcriptional regulators, or engagement of alternative
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activation pathways (24,28,29). For example, recent work suggests that loss of RORγt expression in ILC3
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is accompanied with an upregulation of T-bet and IFNγ expression (24,28). As RORγt is a defining
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transcription factor of ILC3, these cells have been termed ‘ex-ILC3’, but are distinct from ILC1, which have
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no history RORγt expression (33). Collectively, these data suggest that dysregulation or expansion of pro-
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inflammatory ILC populations may directly promote colitis through the production of cytokines IL-17, IL-22,
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TNF-α and IFN-γ.
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promote dysregulation of the composition or functional potential of intestinal ILCs, and further, a role for
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ILC2 in intestinal inflammation.
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Additional studies are required to carefully define the mechanistic pathways that
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Dysregulated ILC responses support intestinal cancers
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In addition to chronic inflammation, dysregulated ILC responses have been linked to the development of
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intestinal cancers. Administration of a carcinogen following Helicobacter hepaticus infection results in the
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formation of aberrant crypt lesions, which were enriched in expression of IL-23, IL-22 and IL-17 (30). ILC3
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and IL-22 were required for cancer progression in this model (30), suggesting that sustained activation of
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ILC3 can promote the formation of intestinal tumors.
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In support of this, it was recently highlighted that uncontrolled IL-22-dependent signals, occurring
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through a loss of the regulatory IL-22 binding protein (IL-22BP), results in increased tumorigenesis in the
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intestine following tissue damage (59). Further, it has also been shown that loss of intestinal barrier
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function can contribute to sustained activation of the IL-23–IL-17 pathway and promote growth of intestinal
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tumors (60). It is possible to speculate that the ILC3–IL-22 axis may be particularly poised to promote
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tumorigenesis by its ability to act directly on intestinal stem cells, as previously observed following
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hematopoietic stem cell transplantation (55).
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In addition to ILC3, recent research suggests that dysregulated intra-epithelial ILC1 responses can
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Therefore, sustained activation of ILCs, likely the result of chronic infection or impaired intestinal
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barrier function, can promote the development and progression of inflammation and cancer within the GI
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tract. Despite these advances, little is known about whether other factors expressed by ILC3, such as LT,
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MHCII or GM-CSF, can in some contexts promote the development of intestinal inflammation or tumors,
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and this will be an important area of future investigation.
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As discussed above, translational studies in healthy human donors and patient populations have revealed
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a significant association of altered intestinal ILC responses with human disease, and basic mouse models
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have demonstrated that ILCs have the functional potential to promote both tissue protective and
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pathologic responses. Therefore, it is likely that developing novel targets to manipulate ILCs will likely be
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of significant value to prevent or limit human intestinal diseases. Additional analyses are required to
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identify the regulatory pathways that control the composition and functional potential of ILC responses in
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the intestine. Recent reports have highlighted that microbial and dietary signals can significantly influence
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intestinal ILCs (43,54,61), suggesting that not only will this be important to consider in our interpretation of
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basic and translational studies, but also that this may be a useful strategy to identify pathways to boost
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protective ILC responses while limiting potentially limiting pathologic ILC responses.
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18 Acknowledgements
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Members of the Sonnenberg laboratory are thanked for discussions and critical reading of the manuscript.
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Research in the Sonnenberg laboratory is supported by the National Institutes of Health (DP5OD012116),
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the NIAID Mucosal Immunology Studies Team (MIST) Scholar Award in Mucosal Immunity, a pilot grant
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from the NIDDK P30 center for Molecular Studies in Digestive and Liver Diseases (P30DK50306) and the
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Institute for Translational Medicine and Therapeutics Transdisciplinary Program in Translational Medicine
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and Therapeutics (UL1-RR024134 from the US National Center for Research Resources).
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Abbreviations
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BAFF, B-cell activating factor; GATA3, GATA-binding protein 3; GI, gastrointestinal; IBD, inflammatory
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bowel disease; Id2, inhibitor of DNA binding 2; ILCs, innate lymphoid cells; NCR, natural cytotoxicity
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Summary and outstanding questions
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receptor,
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immunodeficiency virus; T-bet, T-box expressed in T cells; TCF1, T-cell factor 1; TSLP, thymic stromal
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lymphopoietin.
Ox40L, Ox40 ligand; RORγt, retinoic acid-related orphan receptor γt; SIV, simian
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Figure legends
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Figure 1.
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promote optimal innate and adaptive immunity, maintain immune cell homeostasis and mediate tissue
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repair. This occurs through regulation of multiple epithelial, stromal, granulocyte, myeloid and adaptive
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immune cell lineages.
Intestinal ILCs can
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Figure 2.
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Dysregulated ILC responses, or changes in the composition of ILC populations, can promote chronic
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intestinal inflammation or initiate the development and progression of intestinal tumors. This can occur
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through loss of regulation or sustained activation.
Dysregulated innate lymphoid cell responses can promote intestinal disease.
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Regulation of intestinal health and disease by Innate lymphoid cells
International Immunology
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Manuscript ID: Manuscript Type: Date Submitted by the Author:
Keywords:
Invited Review
02-May-2014
Sonnenberg, Gregory; University of Pennsylvania,
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Complete List of Authors:
INTIMM-14-0065.R1
mucosal immunology, inflammatory bowel disease, intestinal homeostasis, innate lymphoid cells
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Journal:
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International Immunology
Regulation of intestinal health and disease by Innate lymphoid cells
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Gregory F. Sonnenberg
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Division of Gastroenterology, Department of Medicine, and Institute for Immunology, Perelman School of
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Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
7 CORRESPONDENCE Gregory F. Sonnenberg, [email protected]
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Running title: Intestinal innate lymphoid cells
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Keywords: Intestinal homeostasis, mucosal immunology, inflammatory bowel disease, innate lymphoid
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cell.
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Abstract
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Innate lymphoid cells (ILCs) are a recently appreciated immune cell population that is constitutively found
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in the healthy mammalian gastrointestinal (GI) tract and associated lymphoid tissues.
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studies have revealed that alterations in ILC populations are associated with GI disease in patients, such
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as inflammatory bowel disease (IBD), HIV infection and colon cancer, suggesting a potential role for ILCs
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in either maintaining intestinal health or promoting intestinal disease. Mouse models identified that ILCs
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have context-dependent protective and pathologic functions either during the steady state, or following
8
infection, inflammation or tissue damage. This review will discuss the associations of altered intestinal
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ILCs with human GI diseases, and the functional consequences of targeting ILCs in mouse models.
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Collectively, our current understanding of ILCs suggests that the development of novel therapeutic
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strategies to modulate ILC responses will be of significant clinical value to prevent or treat human GI
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diseases.
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Innate lymphoid cells (ILCs) are a family of innate immune cells that critically contribute to the state of
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health or disease in the mammalian gastrointestinal (GI) tract. The development, heterogeneity, plasticity
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and regulation of ILCs have been extensively reviewed elsewhere (1-7). In brief, ILCs develop from
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lymphoid precursors in a process regulated by the common γ-chain cytokine receptor and the transcription
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factors Id2, TCF1 and GATA3. Mature ILCs express the IL-7 receptor (CD127), but lack surface markers
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associated with other immune cell lineages, including T cells, B cells, granulocytes and myeloid cells.
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Further, ILCs can be divided into three groups based on transcriptional regulation. Group 1 ILCs (ILC1)
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constitutively express T-bet but not RORγt, group 2 ILCs (ILC2) constitutively express GATA3 but not
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RORγt, and group 3 ILCs (ILC3) constitutively express RORγt. There are numerous shared regulatory and effector pathways that are associated with each group
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of ILCs. For example, ILC1 respond to IL-12 and IL-18 to produce IFN-γ and TNF-α, ILC2 respond to IL-
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25, IL-33 and TSLP to produce IL-5, IL-9, IL-13 and amphiregulin, and ILC3 respond to IL-1β and IL-23 to
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produce IL-17 and IL-22.
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populations. Currently, ILC1 encompass classical NK cells (which will not be discussed in this review) and
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recently identified ILC1 that lacks expression of eomesodermin and cytolytic potential, and can be
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heterogeneous in expression of natural cytotoxicity receptors (NCRs), such as NKp46 and NKp44. ILC3
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encompass CCR6 cells that most closely resemble fetal lymphoid tissue inducer (LTi) cells and CCR6
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cells that can co-express T-bet and NCRs.
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heterogeneity in groups of ILCs remain unclear and are active areas of investigation.
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However, significant heterogeneity has been found in ILC1 and ILC3
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The lineage relationships, plasticity and significance of
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Analyses of ILCs in humans and mice have revealed that the GI tract and associated lymphoid
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tissues constitutively contain populations of ILCs under homeostatic conditions. Further, studies in patient
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populations with diseases that affect the GI tract, including inflammatory bowel disease (IBD), HIV and
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cancer, have revealed significant alterations in either the composition or the functional potential of ILC
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populations. Mouse models have identified several critical pathways by which ILCs can directly modulate
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intestinal homeostasis, immunity, inflammation and tissue repair, suggesting that further interrogation of
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ILCs could provoke the development of novel preventative and therapeutic strategies for GI diseases. The
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focus of this review will be to discuss data supporting the idea that that alterations in ILC populations occur
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Introduction
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in the intestine of healthy versus diseased humans, and to highlight functional studies in mice identifying
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context-dependent protective and pathologic roles for intestinal ILCs.
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Human innate lymphoid cells in gastrointestinal health and disease
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Subsets of ILCs were first discovered in the intestinal tract and associated lymphoid tissues of fetal and
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adult donors.
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identified—in the tonsils, Peyer’s patches and lamina propria of adult donors—that constitutively
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expressed NKp44, RORC (which encodes RORγ isoforms) and IL-22 (8). Similarly, a report by Cupedo
9
and Spits identified a population of NCR CD127 innate immune cells present in the fetal intestine and
10
mesenteric lymph nodes that expressed IL-17 and IL-22, and further characterized a post-natal
11
development of NKp44 CD127 cells that express IL-22 and RORC in human tonsils (9). Subsequent
12
studies suggested that IL-22-expressing NKp44 cells might be a subset of immature NK cells (10), and
13
highlighted many questions regarding the developmental and lineage relationships of innate IL-22- and IL-
14
17-expressing cell types in the GI tract and associated lymphoid tissues of humans.
In a seminal study by Colonna and colleagues, a subset of innate immune cells was
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Since those initial reports, more recent studies have demonstrated that these cells are indeed a
16
novel innate immune cell population, now termed ILC3, that are distinct from classical NK cells (11) and
17
uniquely regulated by environmental and inflammatory stimuli (12-15).
18
produce IL-22 and IL-17, two cytokines that induce expression of anti-microbial peptides and inflammatory
19
mediators (16), provoked the hypothesis that they were critical regulators of intestinal immunity and
20
inflammation.
The ability of ILC3 to rapidly
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21
Consistent with this, ILC3 were found to be the dominant source of IL-22 in the intestine and
22
associated lymphoid tissue of healthy human donors (17) and, as discussed below, alterations in ILC3
23
populations were identified in multiple infectious, inflammatory and metabolic diseases affecting the GI
24
tract. For example, it was reported by multiple groups that IL-22- and IL-17-expressing ILC3 are depleted
25
from the GI tract of non-human primates following infection with a highly pathogenic strain of simian
26
immunodeficiency virus (SIV) and induction of tissue damage in the intestine (18-20), a pathway critically
27
linked to the progression of AIDS. Further, the presence of IL-22-producing ILC3 populations has been
28
correlated with preserved integrity of the GI tract of HIV-infected individuals (21,22), suggesting a
29
beneficial role for ILC3 and IL-22 in maintaining intestinal health during chronic viral infection.
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IBD patients have also been reported to exhibit significant alterations in intestinal ILCs. IL-22-
2
producing NKp44 ILC3 were found to be reduced in patients with Crohn’s disease (23,24); however,
3
these ILC3 were preserved in ankylosing spondylitis patients exhibiting subclinical intestinal inflammation
4
(25), suggesting that this population of cells may play a role in limiting the development of clinical GI
5
disease. This loss of a potentially ‘protective’ ILC3 population in IBD was also associated with an increase
6
in potentially ‘pathologic’ ILCs (23,24,26). Powrie and colleagues identified an expansion of CD127 IL-
7
23-responsive, IL-17-producing ILC3 in the intestinal lamina propria of Crohn’s disease patients (26). In a
8
seminal study by Spits and colleagues, a subset of IFN-γ-producing ILC1 were found to be increased in
9
Crohn’s disease patients relative to non-inflamed controls, and further expansion of human ILC1 could be
10
driven by experimental intestinal damage in a humanized mouse model (24). Colonna and colleagues
11
also identified a population of T-bet IFN-γ-producing ILC1 residing in the intra-epithelial cell compartment,
12
which accumulated in Crohn’s disease patients (27). Collectively, these reports suggest that there are
13
significant alterations in the composition or functional potential of intestine-resident ILCs during chronic
14
infection or tissue inflammation in humans.
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The mechanisms that result in dysregulated human ILC populations in these chronic diseases
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currently remain unclear.
17
pathologic ILCs may occur through altered lineage plasticity or dysregulated exposure to regulatory
18
cytokines or microbial stimuli (12-14,24,26,28,29). Further, a recent report identified that IL-22 ILC3 are
19
enriched in tumors of patients with colorectal cancer (30), suggesting that alterations in ILCs may be
20
present in a broad spectrum of human GI diseases. Finally, although the presence of ILC2 in the intestine
21
and associated lymphoid tissues has been identified in non-diseased fetal and adult donors (31), it
22
remains poorly defined whether they are dysregulated in the context of intestinal diseases. However, one
23
recent report identified an accumulation of IL-13-producing cells that resemble ILC2 in fibrotic Crohn’s
24
disease patients (32), suggesting an involvement in pathologic collagen deposition. In future analyses of
25
ILCs in the human intestine, it will be important to undertake extensive phenotypic and functional
26
characterization to fully elucidate groups of ILCs in the healthy intestine and alterations that may occur in
27
infectious, inflammatory or metabolic diseases.
Several studies suggest the loss of protective ILCs and accumulation of
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The role of ILCs in maintaining intestinal health
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Functional studies in mice have revealed that ILCs can play a significant role in maintaining intestinal
2
health by promoting immunity to pathogens, limiting inappropriate inflammatory responses to commensal
3
bacteria or dietary antigens, or mediating repair following tissue damage. This is accomplished through
4
expression of a number of factors that can influence stromal, epithelial, myeloid, granulocyte and adaptive
5
immune cell responses (Fig. 1).
6
8
ILCs can be a rapid source of protective cytokines following initial exposure to a variety of pathogens. For
9
example, a recently described ILC1 population was found to be an important innate source of IFN-γ and
10
TNF-α following oral infection with Toxoplasma gondii, which promoted the recruitment of inflammatory
11
monocytes and control of parasite replication (33). ILC2 in the small intestine are critical for promoting
12
tissue immunity via rapid production of IL-5 and IL-13, which induces intestinal goblet cell responses and
13
expulsion of intestinal nematodes, such as Nippostrongylus brasiliensis (34,35). Finally, ILC3 are a rapid
14
source of IL-22 and IL-17, which induce intestinal epithelial cell expression of anti-microbial peptides and
15
innate immunity to extracellular bacteria, such as Citrobacter rodentium (8,16,36,37). Therefore, ILCs
16
provide rapid cytokine production that is critical to control pathogen replication and clearance early
17
following infection.
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As previously reviewed (38), ILCs also play a significant role in modulating adaptive immunity in
19
the intestine through either indirect interactions with stromal cells, or direct interactions with adaptive
20
immune cells. Studies by Mebius and colleagues identified a subset of ILC3, termed lymphoid tissue
21
inducer (LTi) cells, that interacts with stromal cells to induce secondary lymphoid organogenesis prior to
22
birth (39,40). Following birth, a complex interplay between mammalian hosts and commensal bacteria
23
facilitate the maturation of intestinal cryptopatches to isolate lymphoid follicles by RORγt ILC3 (41,42).
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ILC3 promote the development of GALT through expression of lymphotoxin (LT) and interactions
25
with stromal cells, allowing the recruitment of immune cells to discrete organized locations (40). The
26
formation of secondary lymphoid tissues in the intestine by ILC3 is critical for orchestrating optimal
27
adaptive immunity. For example, regulation of these functions of ILC3 by dietary retinoids significantly
28
impacts the magnitude of protective adaptive immune cell responses to mucosal viruses (43). Expression
29
of surface-bound LTα1β2 or soluble LTα3 by ILC3 is also essential for generating host-protective IgA in the
6
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ILCs promote intestinal immunity to pathogens
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GI tract in a T cell-independent and T cell-dependent manner, respectively (44,45). ILC2 have recently
2
been described to regulate eosinophil homeostasis in the intestine through constitutive production of IL-5
3
(46). While the homeostatic functions of intestinal eosinophils are poorly understood, emerging evidence
4
suggests they can contribute to optimal induction of IgA and regulatory T cells (47)
5
ILCs can also directly interact with adaptive immune cells to promote tissue immunity.
ILC3 can
promote B cell responses through production of GM-CSF, BAFF and co-stimulatory receptors, and ILC2
7
have been shown to be critical regulators of B1 cell proliferation (14,34,48).
8
promote maintenance of memory CD4 T cell responses to pathogens through expression of Ox40L and
9
CD30L (49). Collectively, ILCs can orchestrate intestinal immunity to pathogens through rapid cytokine-
11
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ILC3 can also directly
dependent responses, or by facilitating optimal adaptive immune cell responses
ILCs limit inflammatory responses to commensal bacteria and dietary antigens
13
A growing body of evidence suggests that ILCs play a critical role in limiting inappropriate immune
14
responses to non-harmful environmental stimuli, such as commensal bacteria and dietary antigens. In the
15
absence of pathogen infection, loss of ILC3 or IL-22 results in peripheral dissemination of commensal
16
bacteria and systemic inflammation (17). Interestingly, disseminating bacteria were found to be of the
17
genus Alcaligenes or Achromobacter (17), which were characterized to constitutively colonize the GALT of
18
healthy humans, non-human primates and mice (50), suggesting that the ILC3–IL-22 pathway selectively
19
regulates the anatomical containment of commensal bacteria in order to limit chronic inflammation.
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Consistent with this, it has been demonstrated that regulation of ILC3 and IL-22 by the aryl
21
hydrocarbon receptor (Ahr) is critical to limit colonization of intestinal epithelial cells with segmented
22
filamentous bacteria (SFB). Ahr-deficient mice exhibit an overgrowth of SFB and a subsequent increase
23
in pro-inflammatory Th17 cells (51). Collectively, these studies suggest that the ILC3–IL-22 pathway is
24
critical to maintain intestinal homeostasis by limiting the dissemination and replication of commensal
25
bacteria that are intimately associated with mammalian hosts, such as Alcaligenes and Achromobacter
26
that are resident in lymphoid tissue, or SFB that are associated with intestinal epithelial cells.
27
Emerging evidence suggests that ILC3 may also limit inappropriate immune responses to
28
commensal bacteria through other effector pathways. For example, it was recently shown that ILC3 can
29
directly limit pro-inflammatory CD4 T cell responses to commensal bacteria through expression of MHC
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1
class II (MHCII) (52).
2
responses to commensal bacteria and spontaneous intestinal inflammation (52). A recent report by Merad
3
and colleagues also identified that ILC3 are a dominant source of GM-CSF in the intestine and critically
4
regulate myeloid cell homeostasis (53).
5
required to maintain optimal Treg cell responses and tolerance to dietary antigens (53). Collectively, these
6
results suggest that ILC3 play a central role in regulating intestinal homeostasis by limiting inappropriate
7
immune responses to normally beneficial or harmless environmental stimuli.
Loss of ILC-intrinsic MHCII resulted in dysregulated effector CD4 Th17 cell
Intriguingly, ILC3-mediated regulation of myeloid cells was
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ILCs mediate intestinal tissue repair
Production of IL-22 is critical in mediating repair of the intestinal epithelium in the context of tissue damage
11
(16). Studies by Eberl and colleagues have highlighted that ILC3 rapidly respond to experimental tissue
12
damage in the intestine and mediate IL-22-dependent tissue repair (54). Interestingly, in a mouse model
13
of graft versus host disease, ILC3-derived IL-22 maintained intestinal epithelial barrier integrity following
14
hematopoietic stem cell transplantation by directly protecting intestinal stem cells from immune-mediated
15
damage (55). Acting directly on intestinal stem cells may be one mechanism by which a relatively rare
16
population, such as ILC3, can substantially influence homeostasis in the intestine. Collectively, ILCs
17
promote multiple beneficial processes in order to maintain a state of health in the mammalian intestine.
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18 The role of ILCs in promoting intestinal disease
20
In contrast to the tissue protective roles of intestinal ILCs, dysregulated ILC responses or changes in the
21
composition of intestinal ILC populations can promote intestinal inflammation and the development or
22
progression of intestinal cancers (Fig. 2).
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Dysregulated ILC responses promote intestinal inflammation
25
Pioneering research by Powrie and colleagues (56) identified that IL-23 production in response to
26
Helicobacter hepaticus infection, or following dysregulated activation of dendritic cells via anti-CD40
27
antibody administration, results in the expansion of a T-bet ILC3 population that promotes colitis in an IL-
28
17- and IFN-γ-dependent manner. Later research identified that T-bet co-expression in ILC3 is associated
29
with IFN-γ production and enterocolitis following Salmonella infection (57). IL-22 production by ILC3 can
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also promote colitis in some contexts (58), which may be dependent on co-expression of other pro-
2
inflammatory cytokines (16).
4
promote IFN-γ-dependent intestinal inflammation following anti-CD40 antibody administration (27).
5
Emerging evidence suggest that a shift from protective to pathologic ILC responses in the intestine may
6
involve lineage plasticity, altered expression of transcriptional regulators, or engagement of alternative
7
activation pathways (24,28,29). For example, recent work suggests that loss of RORγt expression in ILC3
8
is accompanied with an upregulation of T-bet and IFNγ expression (24,28). As RORγt is a defining
9
transcription factor of ILC3, these cells have been termed ‘ex-ILC3’, but are distinct from ILC1, which have
10
no history RORγt expression (33). Collectively, these data suggest that dysregulation or expansion of pro-
11
inflammatory ILC populations may directly promote colitis through the production of cytokines IL-17, IL-22,
12
TNF-α and IFN-γ.
13
promote dysregulation of the composition or functional potential of intestinal ILCs, and further, a role for
14
ILC2 in intestinal inflammation.
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Additional studies are required to carefully define the mechanistic pathways that
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Dysregulated ILC responses support intestinal cancers
17
In addition to chronic inflammation, dysregulated ILC responses have been linked to the development of
18
intestinal cancers. Administration of a carcinogen following Helicobacter hepaticus infection results in the
19
formation of aberrant crypt lesions, which were enriched in expression of IL-23, IL-22 and IL-17 (30). ILC3
20
and IL-22 were required for cancer progression in this model (30), suggesting that sustained activation of
21
ILC3 can promote the formation of intestinal tumors.
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22
In support of this, it was recently highlighted that uncontrolled IL-22-dependent signals, occurring
23
through a loss of the regulatory IL-22 binding protein (IL-22BP), results in increased tumorigenesis in the
24
intestine following tissue damage (59). Further, it has also been shown that loss of intestinal barrier
25
function can contribute to sustained activation of the IL-23–IL-17 pathway and promote growth of intestinal
26
tumors (60). It is possible to speculate that the ILC3–IL-22 axis may be particularly poised to promote
27
tumorigenesis by its ability to act directly on intestinal stem cells, as previously observed following
28
hematopoietic stem cell transplantation (55).
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In addition to ILC3, recent research suggests that dysregulated intra-epithelial ILC1 responses can
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Therefore, sustained activation of ILCs, likely the result of chronic infection or impaired intestinal
2
barrier function, can promote the development and progression of inflammation and cancer within the GI
3
tract. Despite these advances, little is known about whether other factors expressed by ILC3, such as LT,
4
MHCII or GM-CSF, can in some contexts promote the development of intestinal inflammation or tumors,
5
and this will be an important area of future investigation.
6
8
As discussed above, translational studies in healthy human donors and patient populations have revealed
9
a significant association of altered intestinal ILC responses with human disease, and basic mouse models
10
have demonstrated that ILCs have the functional potential to promote both tissue protective and
11
pathologic responses. Therefore, it is likely that developing novel targets to manipulate ILCs will likely be
12
of significant value to prevent or limit human intestinal diseases. Additional analyses are required to
13
identify the regulatory pathways that control the composition and functional potential of ILC responses in
14
the intestine. Recent reports have highlighted that microbial and dietary signals can significantly influence
15
intestinal ILCs (43,54,61), suggesting that not only will this be important to consider in our interpretation of
16
basic and translational studies, but also that this may be a useful strategy to identify pathways to boost
17
protective ILC responses while limiting potentially limiting pathologic ILC responses.
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18 Acknowledgements
20
Members of the Sonnenberg laboratory are thanked for discussions and critical reading of the manuscript.
21
Research in the Sonnenberg laboratory is supported by the National Institutes of Health (DP5OD012116),
22
the NIAID Mucosal Immunology Studies Team (MIST) Scholar Award in Mucosal Immunity, a pilot grant
23
from the NIDDK P30 center for Molecular Studies in Digestive and Liver Diseases (P30DK50306) and the
24
Institute for Translational Medicine and Therapeutics Transdisciplinary Program in Translational Medicine
25
and Therapeutics (UL1-RR024134 from the US National Center for Research Resources).
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26 27
Abbreviations
28
BAFF, B-cell activating factor; GATA3, GATA-binding protein 3; GI, gastrointestinal; IBD, inflammatory
29
bowel disease; Id2, inhibitor of DNA binding 2; ILCs, innate lymphoid cells; NCR, natural cytotoxicity
10
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Summary and outstanding questions
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receptor,
2
immunodeficiency virus; T-bet, T-box expressed in T cells; TCF1, T-cell factor 1; TSLP, thymic stromal
3
lymphopoietin.
Ox40L, Ox40 ligand; RORγt, retinoic acid-related orphan receptor γt; SIV, simian
4 5
Figure legends
6
Figure 1.
7
promote optimal innate and adaptive immunity, maintain immune cell homeostasis and mediate tissue
8
repair. This occurs through regulation of multiple epithelial, stromal, granulocyte, myeloid and adaptive
9
immune cell lineages.
Intestinal ILCs can
11
Figure 2.
12
Dysregulated ILC responses, or changes in the composition of ILC populations, can promote chronic
13
intestinal inflammation or initiate the development and progression of intestinal tumors. This can occur
14
through loss of regulation or sustained activation.
Dysregulated innate lymphoid cell responses can promote intestinal disease.
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