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Innate Lymphoid Cell-Epithelial Cell Modules Sustain Intestinal Homeostasis

2020; Cell Press; Volume: 52; Issue: 3 Linguagem: Inglês

10.1016/j.immuni.2020.02.016

1097-4180

Andreas Diefenbach, Stylianos Gnafakis, Omer Shomrat,

Immune Cell Function and Interaction

The intestines have the essential but challenging mission of absorbing nutrients, restricting damage from food-derived toxins, promoting colonization by symbionts, and expelling pathogens. These processes are often incompatible with each other and must therefore be prioritized in view of the most crucial contemporary needs of the host. Recent work has shown that tissue-resident innate lymphoid cells (ILCs) constitute a central sensory module allowing adaptation of intestinal organ function to changing environmental input. Here, we propose a conceptual framework positing that the various types of ILC act in distinct modules with intestinal epithelial cells, collectively safeguarding organ function. Such homeostasis-promoting circuitry has high potential to be plumbed for new therapeutic approaches to the treatment of immune-mediated inflammatory diseases. The intestines have the essential but challenging mission of absorbing nutrients, restricting damage from food-derived toxins, promoting colonization by symbionts, and expelling pathogens. These processes are often incompatible with each other and must therefore be prioritized in view of the most crucial contemporary needs of the host. Recent work has shown that tissue-resident innate lymphoid cells (ILCs) constitute a central sensory module allowing adaptation of intestinal organ function to changing environmental input. Here, we propose a conceptual framework positing that the various types of ILC act in distinct modules with intestinal epithelial cells, collectively safeguarding organ function. Such homeostasis-promoting circuitry has high potential to be plumbed for new therapeutic approaches to the treatment of immune-mediated inflammatory diseases. Recent years have witnessed several paradigm shifts in our understanding of multicellular organisms. First, we have come to fully appreciate that living organisms continuously adjust to biotic (e.g., viruses, bacteria, fungi, and parasites colonizing barrier surfaces and collectively referred to as the microbiota) and vital abiotic (e.g., nutrients, light, etc.) factors that they encounter at border surfaces with the environment. Host cells exploit beneficial environmental components and aim to eliminate environmental threats. The ability to carry out this complicated task relies on the capacity of specialized host cells to act as a sensory apparatus for environmental "input," thereby continuously adapting the organism to changes in the environment. This complex sensory apparatus is formed by a collection of different cell types that can communicate with one another. While historically, the detection of abiotic factors was thought to rely almost exclusively on epithelial cells and neurons, and that of biotic factors was perceived to depend solely on immune cells, we now know that these lines are blurry: non-hematopoietic cells, including epithelial cells, do take part in the detection of and response to biotic entities, and immune cell function does partially rely on sensation of abiotic cues. The second major thread of new insight came from data revealing roles for the immune system in the development and function of tissues and organs. Circulating immune cells had long been considered transient inhabitants of organs and tissues, relevant only in settings of immune challenge. We now know that some immune cell types display a fairly sedentary lifestyle in organs and tissues (Fan and Rudensky, 2016Fan X. Rudensky A.Y. Hallmarks of Tissue-Resident Lymphocytes.Cell. 2016; 164: 1198-1211Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). These cells are often deposited into tissues during prenatal development, and they are deeply integrated into the fabric of an organ or tissue, fulfilling tasks that support organ function (Branzk et al., 2018Branzk N. Gronke K. Diefenbach A. Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance.Immunol. Rev. 2018; 286: 86-101Crossref PubMed Scopus (3) Google Scholar, Vivier et al., 2018Vivier E. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. Koyasu S. Locksley R.M. McKenzie A.N.J. Mebius R.E. et al.Innate Lymphoid Cells: 10 Years On.Cell. 2018; 174: 1054-1066Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar). This conceptualization of components of the immune system as integral constituents of barrier organs has led to the exploration of the role played by immune cells in terms of organ function, tissue homeostasis, tissue growth, and repair. Given that we now appreciate that both the immunological and homeostatic functions of an organ depend on both immune and non-immune cells, as well as on environmental cues (such as those from the microbiota), an integrative understanding of the "multicellular meta-organism" is the task of the time (Bosch and McFall-Ngai, 2011Bosch T.C. McFall-Ngai M.J. Metaorganisms as the new frontier.Zoology (Jena). 2011; 114: 185-190Crossref PubMed Scopus (0) Google Scholar). This perspective has had wide ramifications for research informing our understanding of tissue biology. Foremost, the view that epithelial function is regulated solely by epithelial cell-intrinsic signaling circuits has been abandoned. Organ homeostasis and adaptation to components of the environment is maintained by regulatory loops that work similarly to homeostatic circuits. Such a concept entails that environmental factors are continuously sensed by host cells (outside-in signals), and those respond by producing an output signal (inside-out signal) that allows for adaptation of the organ to environmental challenges (Branzk et al., 2018Branzk N. Gronke K. Diefenbach A. Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance.Immunol. Rev. 2018; 286: 86-101Crossref PubMed Scopus (3) Google Scholar). This integrated concept of organ and tissue biology has been, in part, fueled by the advent of single cell technologies that enable the recording of changes in all cells of an organ in the context of various types of infractions to homeostasis (Potter, 2018Potter S.S. Single-cell RNA sequencing for the study of development, physiology and disease.Nat. Rev. Nephrol. 2018; 14: 479-492Crossref PubMed Scopus (36) Google Scholar). Here, we review the current understanding of the mechanisms that underlie immune-epithelial cell interactions, with a focus on the intestines, the largest barrier organ exposed to the most diverse environmental input. We discuss the building blocks of the intestinal epithelial barrier and integrate recent insights into epithelial and immune cell communication, diversity, and function. We propose that tissue-resident immune cells, in particular, innate lymphoid cells (ILCs), act within immune-epithelial cell modules that maintain barrier organ function at steady state and shape the response to changing environmental input. The design principles of the intestine have parallels to other barrier organs like the lung and skin, suggesting that a response framework based on immune-epithelial cell modules is relevant in other tissues. The gut's single-layered epithelial barrier performs a complex and somewhat paradoxical mission: it must show nutrients the "way in" (i.e., it must absorb them), a task requiring close contact with food components. On the other hand, pathogens and toxins—often co-ingested with nutrients—should be shown the "way out," while commensals, which are crucial for optimal fulfilment of both absorption and defense, should be kept in the "corridor" (the lumen). The ability to distinguish between beneficial and harmful components and the occasional need to embark on an all-out war against intestinal pathogens (at the expense of reduced food absorption and damage to intestinal symbiotic microbial communities) depend on highly regulated, multicellular processes that are only partially understood. The intestinal epithelium consists of invaginations, called "crypts," and, in the small intestine, finger-like protrusions, or "villi," which dramatically increase the surface area for absorption (Figure 1). Given the constant mechanical, chemical, and microbial insults encountered by the gut epithelium (Gehart and Clevers, 2019Gehart H. Clevers H. Tales from the crypt: new insights into intestinal stem cells.Nat. Rev. Gastroenterol. Hepatol. 2019; 16: 19-34Crossref PubMed Scopus (48) Google Scholar), its turnover is rapid, with an average lifetime of 3–5 days per cell for most differentiated intestinal epithelial cell (IEC) subsets (Darwich et al., 2014Darwich A.S. Aslam U. Ashcroft D.M. Rostami-Hodjegan A. Meta-analysis of the turnover of intestinal epithelia in preclinical animal species and humans.Drug Metab. Dispos. 2014; 42: 2016-2022Crossref PubMed Scopus (6) Google Scholar). Renewal is driven by the constitutive proliferation of crypt-base columnar (CBC) intestinal epithelial stem cells (ISCs) located at the bottom of the crypts (Barker et al., 2007Barker N. van Es J.H. Kuipers J. Kujala P. van den Born M. Cozijnsen M. Haegebarth A. Korving J. Begthel H. Peters P.J. Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature. 2007; 449: 1003-1007Crossref PubMed Scopus (2988) Google Scholar) and by their differentiation into the mid-crypt-located transit-amplifying (TA) cells, which are highly proliferative precursors on the road toward terminal differentiation into the various IEC types. Two principal subsets of mature IECs can be discriminated: absorptive enterocytes and cells of the secretory lineage. Enterocytes are the most abundant and most fundamental IEC subset: the raison d'être of the intestines is to acquire nutrients and water from the environment, and enterocytes are the IEC subset in charge of absorption. For this task, they are equipped with a plethora of nutrient-digesting enzymes and nutrient transporters. However, the biology of enterocytes is not limited to absorption, as they can participate in fortification of the epithelial barrier, e.g., by secretion of cytokines and antimicrobial peptides (AMPs) (Allaire et al., 2018Allaire J.M. Crowley S.M. Law H.T. Chang S.Y. Ko H.J. Vallance B.A. The Intestinal Epithelium: Central Coordinator of Mucosal Immunity.Trends Immunol. 2018; 39: 677-696Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The small intestine comprises four other prominent IEC subsets, all of which are referred to as "secretory cells": Paneth cells, goblet cells, enteroendocrine cells (EECs), and tuft cells. Importantly, the large intestinal epithelium contains the latter three, but it normally lacks Paneth cells (Allaire et al., 2018Allaire J.M. Crowley S.M. Law H.T. Chang S.Y. Ko H.J. Vallance B.A. The Intestinal Epithelium: Central Coordinator of Mucosal Immunity.Trends Immunol. 2018; 39: 677-696Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Paneth cells, which reside at the crypt base intercalated between CBC, are currently primarily assigned two roles: they can secrete AMP to help protect against microorganisms, and, in addition, they secrete or present factors (WNT, Notch ligands, and EGF) that maintain small intestinal ISCs (Clevers and Bevins, 2013Clevers H.C. Bevins C.L. Paneth cells: maestros of the small intestinal crypts.Annu. Rev. Physiol. 2013; 75: 289-311Crossref PubMed Scopus (283) Google Scholar, Sato et al., 2011Sato T. van Es J.H. Snippert H.J. Stange D.E. Vries R.G. van den Born M. Barker N. Shroyer N.F. van de Wetering M. Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts.Nature. 2011; 469: 415-418Crossref PubMed Scopus (1226) Google Scholar). Importantly, in the large intestine, ISC maintenance seems to require, instead, signals from the poorly characterized REG4+ deep crypt secretory cells (Sasaki et al., 2016Sasaki N. Sachs N. Wiebrands K. Ellenbroek S.I. Fumagalli A. Lyubimova A. Begthel H. van den Born M. van Es J.H. Karthaus W.R. et al.Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon.Proc. Natl. Acad. Sci. USA. 2016; 113: E5399-E5407Crossref PubMed Scopus (76) Google Scholar) (Figure 1). Each Paneth cell is filled with secretory granules containing AMP (and other antimicrobial proteins); release of these granules insulates stem-cell-containing crypts against microbe-related damage (Clevers and Bevins, 2013Clevers H.C. Bevins C.L. Paneth cells: maestros of the small intestinal crypts.Annu. Rev. Physiol. 2013; 75: 289-311Crossref PubMed Scopus (283) Google Scholar). Another important function of the Paneth cell-ISC module is dynamic adaptation to nutritional changes. Under conditions of caloric restriction, Paneth cells act to assure ISC maintenance, at the expense of reduced differentiation into mature IECs (Yilmaz et al., 2012Yilmaz O.H. Katajisto P. Lamming D.W. Gültekin Y. Bauer-Rowe K.E. Sengupta S. Birsoy K. Dursun A. Yilmaz V.O. Selig M. et al.mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake.Nature. 2012; 486: 490-495Crossref PubMed Scopus (343) Google Scholar). The primary function of intestinal goblet cells is the secretion of mucins in order to form protective mucus layers on top of the single-cell layer of epithelial cells (Johansson and Hansson, 2016Johansson M.E. Hansson G.C. Immunological aspects of intestinal mucus and mucins.Nat. Rev. Immunol. 2016; 16: 639-649Crossref PubMed Scopus (163) Google Scholar, Pelaseyed et al., 2014Pelaseyed T. Bergström J.H. Gustafsson J.K. Ermund A. Birchenough G.M. Schütte A. van der Post S. Svensson F. Rodríguez-Piñeiro A.M. 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In the large intestine, whose role in nutrient absorption is more limited, a double mucus layer overlays the epithelium, with a porous outer layer and a dense inner layer (Johansson and Hansson, 2016Johansson M.E. Hansson G.C. Immunological aspects of intestinal mucus and mucins.Nat. Rev. Immunol. 2016; 16: 639-649Crossref PubMed Scopus (163) Google Scholar, Sicard et al., 2017Sicard J.F. Le Bihan G. Vogeleer P. Jacques M. Harel J. Interactions of Intestinal Bacteria with Components of the Intestinal Mucus.Front. Cell. Infect. Microbiol. 2017; 7: 387Crossref PubMed Scopus (47) Google Scholar) (Figure 1). The outer mucus layer is the habitat of most of the microbiota (Sicard et al., 2017Sicard J.F. Le Bihan G. Vogeleer P. Jacques M. Harel J. Interactions of Intestinal Bacteria with Components of the Intestinal Mucus.Front. Cell. Infect. Microbiol. 2017; 7: 387Crossref PubMed Scopus (47) Google Scholar). The inner layer, on the other hand, is normally impenetrable to microbes, creating a region right above the epithelium that is practically devoid of bacteria (Johansson et al., 2008Johansson M.E. Phillipson M. Petersson J. Velcich A. Holm L. Hansson G.C. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria.Proc. Natl. Acad. Sci. USA. 2008; 105: 15064-15069Crossref PubMed Scopus (959) Google Scholar). Mucus is not a static entity, and intestinal microbial communities actively shape mucus density and composition. For example, in the colon, a specialized goblet cell type, termed "sentinel goblet cell," can, upon pathogen sensing, elicit compound exocytosis of mucins from nearby conventional goblet cells, thus aiding in pathogen expulsion (Birchenough et al., 2016Birchenough G.M. Nyström E.E. Johansson M.E. Hansson G.C. 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While EECs are infrequent (~1% of the epithelium), their absolute number renders them the largest endocrine system in the body (Worthington et al., 2018Worthington J.J. Reimann F. Gribble F.M. Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity.Mucosal Immunol. 2018; 11: 3-20Crossref PubMed Scopus (27) Google Scholar). Intestinal EECs are the gut epithelium's "specialists" in all that relates to communicating the nutritional status: they are equipped with a large array of nutrient receptors and can detect the quantity and quality of nutrients in the intestinal lumen. Subsequently, these cells produce hormones and other mediators that inform other cell types—both in their vicinity and in distant organs (including the CNS)—of the nutritional state in the gut, thus affecting digestion, absorption, systemic metabolism, and satiety (Posovszky and Wabitsch, 2015Posovszky C. Wabitsch M. Regulation of appetite, satiation, and body weight by enteroendocrine cells. Part 1: characteristics of enteroendocrine cells and their capability of weight regulation.Horm. Res. Paediatr. 2015; 83: 1-10Crossref PubMed Scopus (13) Google Scholar). Classically, EECs were subdivided into at least 8 distinct subclasses, based on subset-exclusive production of at least one gut hormone. Two single-cell RNA-seq surveys of the small intestinal epithelium revealed more complexity (Gehart et al., 2019Gehart H. van Es J.H. Hamer K. Beumer J. Kretzschmar K. Dekkers J.F. Rios A. Clevers H. Identification of Enteroendocrine Regulators by Real-Time Single-Cell Differentiation Mapping.Cell. 2019; 176: 1158-1173.e1116Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, Haber et al., 2017Haber A.L. Biton M. Rogel N. Herbst R.H. Shekhar K. Smillie C. Burgin G. Delorey T.M. Howitt M.R. Katz Y. et al.A single-cell survey of the small intestinal epithelium.Nature. 2017; 551: 333-339Crossref PubMed Scopus (199) Google Scholar), discovering several different EEC progenitors and numerous EEC subsets, several of which are capable of expressing two or more hormones (or neurotransmitters) whose expression in a single given cell was once thought to be mutually exclusive. EECs also affect and are affected by immune-related challenges in the gut, as will be discussed in detail in later sections. Intestinal tuft cells (named for their characteristic "tuft" of microvilli projecting into the lumen) are another chemosensory type of IEC, and they are enriched for proteins participating in taste-sensing pathways (e.g., α-gustducin and the Ca2+-activated monovalent cation channel TRPM5) (Bezençon et al., 2008Bezençon C. Fürholz A. Raymond F. Mansourian R. Métairon S. Le Coutre J. Damak S. Murine intestinal cells expressing Trpm5 are mostly brush cells and express markers of neuronal and inflammatory cells.J. Comp. Neurol. 2008; 509: 514-525Crossref PubMed Scopus (117) Google Scholar, Howitt et al., 2016Howitt M.R. Lavoie S. Michaud M. Blum A.M. Tran S.V. Weinstock J.V. Gallini C.A. Redding K. Margolskee R.F. Osborne L.C. et al.Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut.Science. 2016; 351: 1329-1333Crossref PubMed Scopus (272) Google Scholar). Like EECs, they too are relatively rare and can be activated by detection of metabolites. The roles of intestinal tuft cells were obscure up until recently. We now appreciate that tuft cells are an important component in type 2 immunity (Figure 1), as will be discussed in detail below. Unsupervised clustering of small intestinal tuft cells based on single-cell transcriptomes revealed two clusters of mature tuft cells, termed "tuft-1" and "tuft-2" (Haber et al., 2017Haber A.L. Biton M. Rogel N. Herbst R.H. Shekhar K. Smillie C. Burgin G. Delorey T.M. Howitt M.R. Katz Y. et al.A single-cell survey of the small intestinal epithelium.Nature. 2017; 551: 333-339Crossref PubMed Scopus (199) Google Scholar). While the transcript signature of the "tuft-1" subset was mostly associated with neuronal development, that of "tuft-2" was strongly linked to immunity. The epithelial lining at barrier surfaces is interspersed and underpinned by a large variety of immune cells collectively referred to as the mucosal immune system. In large parts, research on the mucosal immune system has focused on its roles in pathogen defense, in inflammatory and allergic diseases, and in maintaining a "truce" with environmental components, which can in principle arouse immune responses. Only more recently, it has become clear that mucosal immune cells directly alter epithelial cell function, thereby adapting organ function to changing needs. These insights have been in large parts driven by the discovery of ILC (Spits et al., 2013Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. Koyasu S. Locksley R.M. McKenzie A.N. Mebius R.E. et al.Innate lymphoid cells--a proposal for uniform nomenclature.Nat. Rev. Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1322) Google Scholar). There are three recognized subsets of ILC—ILC1, ILC2, and ILC3—with transcriptional engines and effector programs that mirror those of Th1, Th2, and Th17 cells, respectively. While the parallels to Th cell subsets have attracted considerable attention, eye-opening findings came from studies that linked ILC to functions not usually associated with the immune system. In particular, the various types of ILC seem to form distinct modules with IEC subsets, thereby supporting adaptation of the intestinal organ to changing needs. Such unusual function of ILC is based on various unique attributes of these cells that make them perfectly equipped for such tasks. ILC seed the intestinal organ during fetal development, and they show an extreme tissue sedentary lifestyle and are likely maintained in the tissue lifelong (Bando et al., 2015Bando J.K. Liang H.E. Locksley R.M. Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine.Nat. Immunol. 2015; 16: 153-160Crossref PubMed Scopus (79) Google Scholar, Hoyler et al., 2012Hoyler T. Klose C.S. Souabni A. Turqueti-Neves A. Pfeifer D. Rawlins E.L. Voehringer D. Busslinger M. Diefenbach A. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells.Immunity. 2012; 37: 634-648Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, Kanamori et al., 1996Kanamori Y. Ishimaru K. Nanno M. Maki K. Ikuta K. Nariuchi H. Ishikawa H. 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Lee S.Y. Rudensky A.Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.Science. 2015; 350: 981-985Crossref PubMed Scopus (296) Google Scholar). While ILC2 can expand robustly during worm infections, it is mostly explained by expansion of tissue-resident ILC2 or ILC2 progenitors (Bando et al., 2015Bando J.K. Liang H.E. Locksley R.M. Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine.Nat. Immunol. 2015; 16: 153-160Crossref PubMed Scopus (79) Google Scholar, Gasteiger et al., 2015Gasteiger G. Fan X. Dikiy S. Lee S.Y. Rudensky A.Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.Science. 2015; 350: 981-985Crossref PubMed Scopus (296) Google Scholar). Another unique feature that separates ILC from T cells is that at steady state, they continuously produce their characteristic cytokines and other soluble factors, many of which can directly affect epithelial cell function. While this is true for various cytokines and growth factors produced by ILC, the epitome of such activity has been interleukin (IL)-22, a cytokine that can be produced on demand by T cells but which is tonically produced by ILC3 (Sanos et al., 2009Sanos S.L. Bui V.L. Mortha A. Oberle K. Heners C. Johner C. Diefenbach A. RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells.Nat. Immunol. 2009; 10: 83-91Crossref PubMed Scopus (559) Google Scholar, Savage et al., 2017Savage A.K. Liang H.E. Locksley R.M. The Development of Steady-State Activation Hubs between Adult LTi ILC3s and Primed Macrophages in Small Intestine.J. Immunol. 2017; 199: 1912-1922Crossref PubMed Scopus (13) Google Scholar). The levels of IL-22 available in the gut are tuned by the microbiota (Sanos et al., 2009Sanos S.L. Bui V.L. Mortha A. Oberle K. Heners C. Johner C. Diefenbach A. 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