E-Cadherin Marks a Subset of Inflammatory Dendritic Cells that Promote T Cell-Mediated Colitis

Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK.
Immunity (Impact Factor: 21.56). 04/2010; 32(4):557-67. DOI: 10.1016/j.immuni.2010.03.017
Source: PubMed


Dendritic cells (DCs) play a pivotal role in controlling the balance between tolerance and immunity in the intestine. Gut conditioned CD103(+) DCs promote regulatory T (Treg) cell responses; however, little is known about DCs that drive inflammation in the intestine. Here, we show that monocyte-derived inflammatory DCs that express E-cadherin, the receptor for CD103, promote intestinal inflammation. E-cadherin(+) DCs accumulated in the inflamed mesenteric lymph nodes and colon, had high expression of toll-like receptors, and produced colitogenic cytokines, such as IL-6 and IL-23, after activation. Importantly, adoptive transfer of E-cadherin(+) DCs into T cell-restored immunodeficient hosts increased Th17 cell responses in the intestine and led to exacerbation of colitis. These results identify a monocyte-derived inflammatory DC subset that is associated with the pathogenesis of intestinal inflammation, providing a therapeutic target for the treatment of inflammatory bowel disease.

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    • "In the gut, there are CD103+ DCs that are essential for the steady state of the intestinal mucosa and that finely regulate the number of effector and Treg cells in this tissue (45). However, DC subsets expressing E-cadherin are present in the intestine during IBD and are related to the inflammatory profile found in the disease (46). The number of DCs and other APCs also appear to be increased in experimental colitis and in patients with IBD (44). "
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    ABSTRACT: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 07/2014; DOI:10.1590/1414-431X20143932 · 1.01 Impact Factor
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    • "In mice, E-Cadherin marks a murine colitogenic DC subset that can be directly recruited from the blood to the mLNs (Siddiqui et al., 2010), whereas the CD103  CX 3 CR1 + mononuclear gut phagocytes originate from Ly6C high monocytes that are recruited to the inflamed mucosal tissues and differentiate into CX 3 CR low CD11b + cells (Bar-On et al., 2011; Rivollier et al., 2012; Bain et al., 2013). Further phenotypic analysis revealed that a significant proportion of the HLA- DR + CD172a + cells expressed E-Cadherin or CX 3 CR1 in lymphoid and nonlymphoid CD tissues (Fig. 1 C). "
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    ABSTRACT: In mice, the transfer of CD172a(+) (SIRP-α) dendritic cells (DCs) elicits T cell-driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn's disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX3CR1. Spontaneous IL-1β and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR(-)CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD.
    Journal of Experimental Medicine 05/2013; 210(6). DOI:10.1084/jem.20122037 · 12.52 Impact Factor
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    • "Based on the short kinetic of differentiation observed in vivo, it is likely that so called " DC genes " are poised to enable rapid differentiation into MoDCs to efficiently counter pathogen attack. The characterization of new markers that clearly identify MoDCs from cDCs in inflamed tissues will open the door for a better understanding of the molecular mechanisms that drive monocyte differentiation into MoDCs (Cheong et al., 2010; Siddiqui et al., 2010). "
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    ABSTRACT: Dendritic cells (DCs) are specialized antigen presenting cells that are exquisitely adapted to sense pathogens and induce the development of adaptive immune responses. They form a complex network of phenotypically and functionally distinct subsets. Within this network, individual DC subsets display highly specific roles in local immunosurveillance, migration, and antigen presentation. This division of labor amongst DCs offers great potential to tune the immune response by harnessing subset-specific attributes of DCs in the clinical setting. Until recently, our understanding of DC subsets has been limited and paralleled by poor clinical translation and efficacy. We have now begun to unravel how different DC subsets develop within a complex multilayered system. These findings open up exciting possibilities for targeted manipulation of DC subsets. Furthermore, ground-breaking developments overcoming a major translational obstacle - identification of similar DC populations in mouse and man - now sets the stage for significant advances in the field. Here we explore the determinants that underpin cellular and transcriptional heterogeneity within the DC network, how these influence DC distribution and localization at steady-state, and the capacity of DCs to present antigens via direct or cross-presentation during pathogen infection.
    Frontiers in Immunology 02/2012; 3:26. DOI:10.3389/fimmu.2012.00026
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