Mucosal Regulatory System for Balanced Immunity in the Gut

C H A P T E R

15 Mucosal Regulatory System for Balanced Immunity in the Gut Hisako Kayama1,2,3 and Kiyoshi Takeda1,2,3 1

Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Japan 2WPI Immunology Frontier Research Center, Osaka University, Suita, Japan 3Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan

I. INTRODUCTION In the intestinal mucosa, the immune system is balanced between activating proinflammatory pathways for host defense against invading pathogens and remaining unresponsive to symbiotic microorganisms and dietary antigens. Because constitutive or excessive activation of immune responses causes intestinal tissue destruction, various immune cells contribute to the induction of tolerance for the maintenance of gut homeostasis as well as driving proinflammatory responses to pathogens. The two major forms of inflammatory bowel disease (IBD) are ulcerative colitis (UC) and Crohn’s disease (CD), both of which are characterized by chronic relapsing-remitting courses [1]. Excessive adaptive immune responses such as T helper (Th)1 and Th17 cell responses are implicated in the pathogenesis of IBD [2]. In the intestinal mucosa, antiinflammatory cytokine

Mucosal Vaccines DOI: https://doi.org/10.1016/B978-0-12-811924-2.00015-8

interleukin-10 (IL-10)-producing CD41 T cells such as Foxp31 regulatory cells (Tregs) and Foxp32 type 1 regulatory T (Tr1) cells comprise the major regulatory cells in the adaptive immune system [3]. IL-10 produced by Foxp31 Tregs and Tr1 cells is thought to regulate the activity of innate myeloid cells in the intestine [4] and thereby prevent intestinal inflammation. In addition to IL-10, Foxp31 Tregs inhibit inflammatory responses by producing antiinflammatory cytokine transforming growth factor beta (TGF-β) as well as by expressing CTLA-4, LAG-3, CD39, and Nrp-1 [5]. During chronic inflammation, regulatory B cells (Breg) develop and suppress inflammatory responses through the production of IL-10 and TGF-β [6]. CD1d expression on Bregs is required for the production of IL-10. Accordingly, Bregs lacking Cd1d are unable to suppress the exacerbation of intestinal inflammation [7]. The transfer of IL10-producing Bregs induced by IL-33 had a

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therapeutic effect on colitis in Il102/2 mice [8]. These studies demonstrate that regulatory cells in the adaptive immune system are required for sustained intestinal immune balance and thereby repress enteric inflammation. Because innate myeloid cells can shape adaptive immunity through antigen presentation and cytokine production via the activation of pattern recognition receptors, such as tolllike receptors (TLRs) [9 12], the dysregulation of the innate immune system is linked to the inadequate activation of adaptive immunity and thus is implicated in the pathogenesis of IBD. Recent studies have identified a variety of innate myeloid cell subsets that modulate intestinal immune responses in the murine gut [13]. Among these subsets, some innate myeloid

cells promote intestinal inflammation by activating colitogenic effector T cells through the upregulation of gut-homing receptor α4β7 [14] and the production of proinflammatory cytokines such as IL-6 and IL-23, both of which induce Th17 responses [15]. Accordingly, patients with CD have abnormal intestinal macrophages with IL-23-induced interferon gamma (IFN-γ) production and enhanced antigen-presenting activity [16,17]. These findings indicate that intestinal innate immunity might be tightly controlled to maintain gut homeostasis and that its dysregulation might be associated with the pathogenesis of IBD. This chapter focuses on the role of murine (Fig. 15.1) and human (Fig. 15.2) intestinal innate myeloid cells in the organization of

FIGURE 15.1 Maintenance of immunological tolerance by murine intestinal innate myeloid cells. (A, B) CD1031 DCs

induce Foxp31 Tregs through the production of TGF-β and retinoic acid (RA) (A) or indoleamine 2,3-dioxygenase (IDO) (B). (C) CD1031 CD11b2 DCs activated by probiotic Bifidobacterium breve induce IL-10-producing Tr1 cells through the production of IL-10 and IL-27. (D) Proinflammatory cytokine production, such as IL-12 and IL-23, by intestinal CX3CR1high macrophages is tightly regulated by an IL-10/Stat3 axis-dependent mechanism. (E) Intestinal CX3CR1high macrophages in the large intestinal lamina propria inhibit CD41 T cell proliferative responses through the high expression of adhesion molecules such as ICAM-1 and VCAM-1 and lower expression of CD80/CD86. (F) IL-10 produced by intestinal CX3CR1high macrophages maintains Foxp31 Tregs.

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II. INDUCTION OF INTESTINAL IMMUNE TOLERANCE BY CD103 1 DENDRITIC CELLS

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FIGURE 15.2

Regulation of gut homeostasis and ulcerative colitis by human intestinal innate myeloid cells. (A) In the colon of healthy individuals, CD1031 DCs induce the FOXP31 Tregs. (B) Colonic CD1031 DCs from patients with ulcerative colitis (UC) decrease FOXP31 Treg-inducing activity but markedly increase the ability to promote development of Th1, Th2, and Th17 cells with higher expressions of IL6, IL23A, IL12p35, and TNF. (C) CD141 CD163high CD160high cells constitutively produce IL-10 and inhibit effector CD41 T cell proliferation. (D) In UC patients, the number of CD141 CD163high CD160high cells is markedly decreased. In addition, CD163high CD160high cells from UC patients do not suppress effector CD41 T cell proliferative responses.

mucosal regulatory systems for maintenance of the gut homeostasis.

II. INDUCTION OF INTESTINAL IMMUNE TOLERANCE BY CD1031 DENDRITIC CELLS Mononuclear phagocytes in the murine intestine have been characterized into a variety of subsets with distinct abilities to either promote or inhibit T cell responses for the maintenance of gut homeostasis [18,19]. In particular, murine intestinal CD1031 dendritic cells (DCs) and CX3CR11 CD11b1 cells have been well characterized. Among CD1031 DCs, CD1031 CD11c1 DCs promote the proliferation of CD41

and CD81 T cells [20], induce cytotoxic T lymphocytes [21], regulate antimicrobial peptide expression in epithelial cells by inducing IL-22 production by innate lymphoid cells through flagellin-dependent IL-23 production [22], and induce Th1 and Th17 cell differentiation [23,24]. In addition to mucosal defense, CD1031 DCs contribute to intestinal tolerance by inducing Foxp31 Tregs through the production of TGF-β and retinoic acid, which is a metabolite of vitamin A [25] (Fig. 15.1A). In addition, CD1031 DCs promote the differentiation of Foxp31 Tregs through expression of indoleamine 2,3dioxygenase (IDO), which is a tryptophan catabolism enzyme [26] (Fig. 15.1B). Accordingly, the inhibition of IDO disrupted oral tolerance and exacerbated intestinal

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inflammation [26]. In the colon, CD1031 CD11b2 DCs activated by probiotic Bifidobacterium breve via the TLR2/MyD88 pathway produce IL-10 and IL-27 and thereby induce IL-10-producing Tr1 cells [27] (Fig. 15.1C). In addition, oral B. breve administration improved T-cell-mediated colitis in an IL-10-dependent manner. Thus CD1031 DCs play multiple roles in the induction of immune tolerance as well as effector responses against pathogens in the gut.

III. REGULATION OF IMMUNE HOMEOSTASIS BY INTESTINAL RESIDENT CX3CR1HIGH MACROPHAGES Intestinal CX3CR11 CD11b1 cells are heterogeneous and can be further divided into CX3CR1high CD11b1 macrophages and intermediate (int) CX3CR1 CD11b1 DCs [28,29]. CX3CR1int CD11b1 DCs promote inflammatory responses by inducing the differentiation of Th17 cells [30,31]. CX3CR1high CD11b1 cells are intestinal resident macrophages [32]. CX3CR1high macrophages in the intestinal lamina propria of neonates arise from embryonic precursors in the yolk sac [33], whereas both CX3CR1int DCs and CX3CR1high macrophages in the intestine of adult mice are derived from blood Ly6Chigh CCR21 monocytes [34 36]. A recent study showed that miR-223 deficiency resulted in a decreased number of intestinal CX3CR1high macrophages and severe dextran sodium sulfate-induced colitis [37], suggesting that the appropriate differentiation and function of intestinal CX3CR1high macrophages are required for sustained gut homeostasis. Intestinal CX3CR1high macrophages are nonmigratory cells even under inflammatory conditions [23,38]. A previous study showed that the migration of intestinal CX3CR1high macrophages from the lamina propria to mesenteric lymph nodes was suppressed by a commensal

bacteria-dependent mechanism and inhibited the activation of T cell responses and IgA production [39]. Intestinal CX3CR1high macrophages are crucial for host defense against invading pathogens based on their high phagocytic activity [35]. To maintain immune tolerance in the gut, intestinal CX3CR1high macrophages mediate their noninflammatory features via IL-10 receptor signaling-dependent mechanisms [4,40] (Fig. 15.1D). A previous study revealed that the myeloid lineage cellspecific deletion of Stat3, a downstream transcription factor of the IL-10 signaling pathway, resulted in the spontaneous development of colitis with the hyperproduction of proinflammatory cytokines such as IL-12, IL-6, and tumor necrosis factor alpha (TNF-α) by innate myeloid cells [41]. In addition, large intestinal CX3CR1high macrophages from Il102/2 mice showed the increased production of proinflammatory cytokines, including IL-12 and IL-23 [34], suggesting that the expression of a subset of proinflammatory cytokines that mediate the induction/activation of colitogenic Th1 and Th17 cells in intestinal CX3CR1high macrophages might be tightly regulated by an IL-10/ Stat3 axis-dependent mechanism. Furthermore, CX3CR1high macrophages in the large intestinal lamina propria acquire their activity to inhibit CD41 T cell proliferative responses through the IL-10/Stat3 signaling pathway and thereby prevent intestinal inflammation [29]. Large intestinal CX3CR1high macrophages preferentially interacted with effector CD41 T cells through the high expression of adhesion molecules such as ICAM-1 and VCAM-1. However, these cells did not activate CD41 T cells because their expression of CD80/CD86 was severely suppressed via IL-10/Stat3 signaling [29]. In comparison to other tissue-resident macrophages, intestinal CX3CR1high macrophages produce a large amount of IL-10 constitutively, which maintained Foxp31 Tregs [42]. In addition, autocrine IL-10 signals from intestinal CX3CR1high macrophages suppressed

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IV

ROLES OF HUMAN INTESTINAL MYELOID CELLS

colitogenic IL-23 production [43]. Thus murine intestinal CX3CR1high CD11b1 cells are unique tissue-resident macrophages with regulatory properties. Small intestinal CX3CR1high macrophages develop by a Notch signaling-dependent mechanism [44]. CX3CR1high macrophages residing in the small intestine possess another unique property allowing them to extend their dendrites directly into the intestinal lumen. The transepithelial sampling of microbes by CX3CR1high macrophages in the small intestine is dependent on CX3CR1 expression. Accordingly, in CX3CR1-deficient mice, the sampling of entero-invasive pathogens by small intestinal innate myeloid cells was impaired, and their susceptibility to Salmonella enterica serovar Typhimurium was enhanced [45]. In addition to CX3CR1, TLR/MyD88 signaling pathways in intestinal epithelial cells are required for dendrite extension by CX3CR1high macrophages [46]. Recently, a study showed that CX3CR1high macrophages contributed to the induction of Foxp31 Treg cell-mediated tolerance to a food antigen by taking up soluble fed antigen and transferring it to CD1031 DCs via a gap-junction-mediated mechanism [47]. Thus small intestinal CX3CR1high macrophages contribute to sustained immunological tolerance through the sampling of luminal antigens.

IV. ROLES OF HUMAN INTESTINAL MYELOID CELLS IN THE MAINTENANCE OF GUT HOMEOSTASIS AND INFLAMMATORY BOWEL DISEASE Similar to CD1031 DCs in the murine intestine, human intestinal CD1031 DCs induce the expression of gut-homing receptors, such as CCR9 and integrin α4β7, on T cells [20]. In the human small intestine, CD1031 Sirpα2 DCs, equivalent to murine CD1031 CD11b2 DCs, evoke Th17 cell differentiation [48]. In addition,

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CD1031 Sirpα1 DCs, equivalent to murine CD1031 CD11b1 DCs, induce FOXP31 Tregs as well as Th17 cells [48]. In the colon, CD1031 DCs from healthy individuals induced the conversion of naı¨ve T cells into FOXP31 Tregs but not into Th1 or Th17 cells [49] (Fig. 15.2A). In contrast, colonic CD1031 DCs from UC patients showed decreased in FOXP31 Treg-inducing activity but exhibited a marked increase in the development of Th1, Th2, and Th17 cells, with higher expression of proinflammatory cytokine genes IL6, IL23A, IL12p35, and TNF (Fig. 15.2B). In the human intestinal mucosa, CD141 macrophages are increased in CD patients and produce greater amounts of inflammatory cytokines, such as IL-6, IL-23, and TNF-α, in response to commensal bacteria [16]. In addition, CD141 macrophage-derived IL-23 facilitates colitogenic IL-17 and IFN-γ-producing CD41 T cell differentiation [16,17,50,51]. Human intestinal HLA-DRhigh CD141 innate myeloid cells are further characterized as CD141 CD163low cells and CD141 CD163high cells. CD141 CD163low cells induce Th17 cell differentiation by producing Th17-related cytokines, such as IL-6, IL-23p19, TNF-α, and IL-1β, through TLR2, TLR4, and TLR5 signaling pathways [52]. In CD patients, the activity of CD141 CD163low cells to induce Th17 cells is increased. CD141 CD163high cells can be subdivided into two subsets, CD141 CD163high CD160high and CD141 CD163high CD160low cells, based on the expression levels of CD160 [53]. Similar to murine intestinal CX3CR1high macrophages, CD141 CD163high CD160high cells constitutively produce high amounts of IL-10 and exert high phagocytic activity. In addition, CD141 CD163high CD160high cells inhibit effector CD41 T cell proliferation in a FOXP31 Tregindependent manner (Fig. 15.2C). In the colon of UC patients, the number of CD141 CD163high CD160high cells is markedly decreased. In this context, CD163high CD160high cells show higher CD80/CD86 expression with

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decreased IL10RB expression. Furthermore, CD163high CD160high cells from UC patients do not suppress effector CD41 T cell proliferative responses (Fig. 15.2D). Thus several regulatory innate myeloid cells, including CD1031 DCs and CD141 CD163high CD160high cells, are crucial for balanced immunity in the human and murine intestine.

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[8]

V. CONCLUDING REMARKS In the intestinal mucosa, appropriate effector T cell responses play an important role in protection against invading pathogens in the steady state, whereas their excessive activation leads to intestinal inflammation. Recent advances have demonstrated the key roles of intestinal innate immune cells in immunological tolerance through the regulation of the adaptive immune system to maintain gut homeostasis. Further human studies to characterize the innate and adaptive immune systems responsible for either the maintenance of gut homeostasis or the pathogenesis of intestinal inflammation will advance diagnostic and therapeutic approaches for IBD.

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Acknowledgments We thank C. Hidaka for secretarial assistance and J.L. Croxford, PhD, from Edanz Group (www.edanzediting. com/ac) for editing a draft of this manuscript.

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