Steady-state migrating intestinal dendritic cells induce potent inflammatory responses in naive CD4+T cells (original) (raw)
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Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract
Journal of Experimental Medicine, 2013
and CCR9 by Peyer's patch and mesenteric lymph node (MLN) dendritic cells (DCs) in a retinoic acid-dependent manner. This paradigm, however, cannot be reconciled with reports of GI T cell responses after intranasal (i.n.) delivery of antigens that do not directly target the GI lymphoid tissue. To explore alternative pathways of cellular migration, we have investigated the ability of DCs from mucosal and nonmucosal tissues to recruit lymphocytes to the GI tract. Unexpectedly, we found that lung DCs, like CD03 + MLN DCs, up-regulate the gut-homing integrin 47 in vitro and in vivo, and induce T cell migration to the GI tract in vivo. Consistent with a role for this pathway in generating mucosal immune responses, lung DC targeting by i.n. immunization induced protective immunity against enteric challenge with a highly pathogenic strain of Salmonella. The present report demonstrates novel functional evidence of mucosal cross talk mediated by DCs, which has the potential to inform the design of novel vaccines against mucosal pathogens.
Inflammatory Bowel Diseases, 2006
We examined ileal dendritic cell (DC) subpopulations in a rat model of indomethacin-induced enteritis to determine changes in phenotype and distribution associated with increased mucosal permeability during acute and chronic stages of inflammation. Sprague-Dawley rats were treated with indomethacin (7.5 mg/kg subcutaneously, 2 injections 48 h apart). Animals were killed at day 4 (acute stage) or at day 15 or 30 (chronic stages); control rats were injected with saline. DC distribution was evaluated by immunohistochemistry for CD103, CD11b, CD83, and CD163; inflammation was assessed by light microscopy; and permeability was determined by flux of horseradish peroxidase in Ussing chambers. In controls, both immature DC subpopulations, CD103 + CD11b + CD163 j CD83 j and CD103 + CD11b j CD163 j CD83 j , were observed in the lamina propria, and the CD11b j population also was present in Peyer`s patches. In acute inflammation, permeability was increased (P G 0.01), and inflamed areas with or without ulcers were observed. CD103 + and CD11b + (CD83 j ) DCs were absent from inflamed areas, reduced in noninflamed tissues, but present in Peyer`s patches. In the chronic stage at day 15, CD103 + and CD11b + cells were located in inflamed and noninflamed areas and in Peyer`s patches. In addition, CD83 + DCs were detected in inflamed areas. At day 30, when we observed a complete microscopic resolution of inflammation, numbers of CD103 + and CD11b + DCs were increased, and there were CD83 + DCs beneath the epithelial cell layer. We conclude that antigen uptake in acute inflammation may activate resident immature DCs, inducing their migration to lymphoid tissue where they mature and then return to the intestine to play a role in the local inflammatory response.
Mucosal Immunology, 2015
Tolerance to harmless exogenous antigens is the default immune response in the gastrointestinal tract. Although extensive studies have demonstrated the importance of the mesenteric lymph nodes (MLNs) and intestinal CD103 þ dendritic cells (DCs) in driving small intestinal tolerance to protein antigen, the structural and immunological basis of colonic tolerance remain poorly understood. We show here that the caudal and iliac lymph nodes (ILNs) are inductive sites for distal colonic immune responses and that colonic T cell-mediated tolerance induction to protein antigen is initiated in these draining lymph nodes and not in MLNs. In agreement, colonic tolerance induction was not altered by mesenteric lymphadenectomy. Despite tolerance development, CD103 þ CD11b þ DCs, which are the major migratory DC population in the MLNs, and the tolerance-related retinoic acid-generating enzyme RALDH2 were virtually absent from the ILNs. Administration of ovalbumin (OVA) to the distal colon did increase the number of CD11c þ MHCII hi migratory CD103 À CD11b þ and CD103 þ CD11b À DCs in the ILNs. Strikingly, colonic tolerance was intact in Batf3deficient mice specifically lacking CD103 þ CD11b À DCs, suggesting that CD103 À DCs in the ILNs are sufficient to drive tolerance induction after protein antigen encounter in the distal colon. Altogether, we identify different inductive sites for small intestinal and colonic T-cell responses and reveal that distinct cellular mechanisms are operative to maintain tolerance at these sites.
Plasmacytoid Dendritic Cells Do Not Migrate in Intestinal or Hepatic Lymph
The Journal of Immunology, 2006
Plasmacytoid dendritic cells (pDCs) recognize pathogen-associated molecules, particularly viral, and represent an important mechanism in innate defense. They may however, also have roles in steady-state tolerogenic responses at mucosal sites. pDCs can be isolated from blood, mucosa, and lymph nodes (LNs). Although pDCs can express peripherally derived Ags in LNs and at mucosal sites, it is not clear whether pDCs actually migrate from the periphery in lymph or whether LN pDCs acquire Ags by other mechanisms. To determine whether pDCs migrate in lymph, intestine or liver-draining LNs were removed and thoracic duct leukocytes (TDLs) were collected. TDLs expressing MHC-II and CD45R, but not TCR␣ or CD45RA, were then analyzed. These enriched TDLs neither transcribe type I IFNs nor secrete inflammatory cytokines in response to viral stimuli in vitro or after a TLR7/8 stimulus in vivo. In addition, these TDLs do not express CD5, CD90, CD200, or Siglec-H, but do express Ig, and therefore represent B cells, despite their lack of CD45RA expression. Intestinal and hepatic lymph are hence devoid of bona fide pDCs under both steady-state conditions and after TLR7/8 stimulation. This shows that any role for pDCs in Ag-specific T cell activation or tolerance must differ from the roles of classical dendritic cells, because it cannot result from peripheral Ag capture, followed by migration of pDCs via lymph to the LN.
Differential regulation of dendritic cell–T cell cross talk in the gut-associated lymphoid tissue
Molecular Immunology, 2006
Dendritic cells (DC) play a central role in the regulation of immune responses by processing and presenting antigens to naïve T cells. It has been proposed that after the initial interaction between DC and T cells, T cell-induced DC apoptosis serves as a down-regulatory mechanism that prevents the otherwise continuous activation of T cells by antigen-bearing DC. Our aim was to investigate and compare the susceptibility of Peyer's patch (PP)-derived and systemic (splenic) DC to antigen-specific T cell-mediated apoptosis in mice of different genetic background. Freshly isolated CD11c +/hi B220 − DC from intestinal Peyer's patch and spleen from Balb/c and C3H/HeJ mice were co-cultured with syngeneic antigen-specific T cells in the presence or absence of the relevant antigen. In both mouse strains PP-DC showed higher susceptibility to T cell-mediated apoptosis compared to splenic ones, but levels of DC apoptosis were overall higher in C3H/HeJ mice compared to Balb/c. DC apoptosis was induced by both Th1 and Th2 antigen-specific clones and was strictly MHC class II-dependent in both strains, and interestingly we observed that although CD95-CD95L ligation played an overall minor part in T cell-induced DC apoptosis its role varied according to the mouse strain. Here, we demonstrated that PP-DC and splenic DC significantly differed in regard to their susceptibility to T cell-mediated killing. We interpreted these data as showing that the reciprocal regulation between DC and T cells in the gastrointestinal immune system is under stricter control compared to the systemic immune system and we hypothesized that these events are likely to contribute to the generation of fine balanced responses to intestinal antigens.
Regulation of Intestinal Immune System by Dendritic Cells
Immune Network, 2015
Innate immune cells survey antigenic materials beneath our body surfaces and provide a front-line response to internal and external danger signals. Dendritic cells (DCs), a subset of innate immune cells, are critical sentinels that perform multiple roles in immune responses, from acting as principal modulators to priming an adaptive immune response through antigen-specific signaling. In the gut, DCs meet exogenous, non-harmful food antigens as well as vast commensal microbes under steady-state conditions. In other instances, they must combat pathogenic microbes to prevent infections. In this review, we focus on the function of intestinal DCs in maintaining intestinal immune homeostasis. Specifically, we describe how intestinal DCs affect IgA production from B cells and influence the generation of unique subsets of T cell.
Intestinal dendritic cells increase T cell expression of α4β7 integrin
European Journal of Immunology, 2002
The integrin § 4 g 7 binds to MAdCAM-1 and contributes to homing of lymphocytes to gut and other mucosal tissues. In humans, the § 4 g 7 hi subset of circulating memory cells appears to have been primed in mucosal tissues. The factors that determine whether § 4 g 7 lo naive cells become § 4 g hi or § 4 g 7cells upon differentiation are poorly understood but could include an influence of the activating antigen-presenting cell. To address this point, the induction of § 4 g 7 following activation of mouse cells with the APC-dependent stimulus soluble anti-CD3 has been examined. Almost all mouse T cells freshly isolated from mesenteric lymph nodes (MLN) and peripheral (PLN; axillary, brachial and inguinal) lymph nodes stained only weakly for § 4 g 7 but a subpopulation became § 4 g 7 hi upon activation with anti-CD3 in a cell cycleand accessory cell-dependent manner. A small proportion (approximately 1.5 %) of the starting cells gave rise to § 4 g 7 hi cells after culture. A higher proportion of § 4 g 7 hi cells were generated in MLN than PLN cultures. Peyer's patch cultures gave intermediate values.
Inflammatory Bowel …, 2004
Ulcerative colitis and Crohn's disease, collectively termed inflammatory bowel diseases (IBD), are chronic inflammatory diseases of the intestine that afflict more than 4 million people worldwide. Intestinal inflammation is characterized by an abnormal mucosal immune response to normally harmless antigens in the gut flora. In Crohn's disease, the pathogenic mucosal immune response is a typical T helper (T H 1) type cell response, whereas ulcerative colitis is predominantly associated with a T H 2 response. We are interested in the role of dendritic cells in early immunologic events leading to T cell activation and chronic intestinal inflammation. Using a murine adoptive transfer model of IBD, we found an accumulation of dendritic cells in colon and mesenteric lymph nodes during the early stage of IBD before the appearance of epithelial lesions and tissue degradation. In situ immunostaining and flow-cytometric analysis revealed that approximately 50% of colonic dendritic cells were CD11b + B220 − myeloid dendritic cells and 50% expressed the CD11b − B220 + plasmacytoid phenotype. In corresponding mesenteric lymph nodes, approximately 16% were plasmacytoid dendritic cells. Colonic myeloid dendritic cells were shown to express the co-stimulatory molecule CD40. Both, colonic myeloid and plasmacytoid dendritic cells released interferon-␣ in situ and stimulated T cell proliferation ex vivo. Our results show that dendritic cells can mature in the intestine without migrating to mesenteric lymph nodes. Mature intestinal dendritic cells may form a nucleation site for a local T cell response and play an important role in the pathogenesis of IBD.