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Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract.

ABSTRACT: Developing efficacious vaccines against enteric diseases is a global challenge that requires a better understanding of cellular recruitment dynamics at the mucosal surfaces. The current paradigm of T cell homing to the gastrointestinal (GI) tract involves the induction of ?4?7 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 CD103(+) MLN DCs, up-regulate the gut-homing integrin ?4?7 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.

SUBMITTER: Ruane D

PROVIDER: S-EPMC3754860 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract.

Ruane Darren D Brane Lucas L Reis Bernardo Sgarbi BS Cheong Cheolho C Poles Jordan J Do Yoonkyung Y Zhu Hongfa H Velinzon Klara K Choi Jae-Hoon JH Studt Natalie N Mayer Lloyd L Lavelle Ed C EC Steinman Ralph M RM Mucida Daniel D Mehandru Saurabh S

The Journal of experimental medicine 20130819 9

Developing efficacious vaccines against enteric diseases is a global challenge that requires a better understanding of cellular recruitment dynamics at the mucosal surfaces. The current paradigm of T cell homing to the gastrointestinal (GI) tract involves the induction of α4β7 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.) ...[more]

PMID: 23960190

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Project description:Stress negatively affects the gastrointestinal tract (GIT) barrier function, resulting in compromised animal health. A deeper understanding of how diet and stress impacts the GIT barrier function in feedlot cattle is needed. Aspirin decreases mucus production and mucosal repair in the GIT and could be used as a model for GIT barrier dysfunction research. The objective of this study was to evaluate the effectiveness of aspirin to induce GIT barrier dysfunction in beef cattle. In experiment 1, sixteen crossbred heifers (425.0 ± 8.6 kg) were allotted to 0, 50, 100, or 200 mg/kg body weight (BW) aspirin doses based on BW. Experiment 1 consisted of two periods separated by 4 wk where four heifers per treatment received the same aspirin dose during each period. Heifers were fed a 49.4% corn silage and 50.6% concentrate diet. The 200 mg/kg BW aspirin treatment was dosed as a 100 mg/kg BW aspirin oral bolus 36 and 24 h prior to Cr-ethylenediaminetetraacetic acid (EDTA) dosing (1 liter; 180 mM). The 50 and 100 mg/kg BW aspirin treatments were dosed as an oral bolus 24 h prior to Cr-EDTA dosing. Urine was collected every 3 h for 48 h and analyzed for Cr. Serum was collected at 0 and 48 h and analyzed for lipopolysaccharide-binding protein (LBP), interleukin-6, serum amyloid A (SAA), haptoglobin, and aspartate aminotransferase. In experiment 2, sixteen crossbred steers (576.0 ± 14.2 kg) fed a similar diet were allotted by BW to the 0 and 200 mg/kg BW aspirin treatments (eight steers/treatment) and were slaughtered 24 h after the last dose. Jejunal tissues were collected, and claudin (CLDN) 1, 2, and 3, occludin, and zonula occludens tight junction messenger ribonucleic acid (mRNA) expression was determined. Data were analyzed using the MIXED procedure of SAS. Urinary Cr excretion increased linearly at hours 3, 6, 9, and 12 (P ≤ 0.04) as aspirin dose increased from 0 to 200 mg/kg. Aspirin linearly increased Cr absorption (P = 0.02) and elimination (P = 0.04) rates and linearly decreased mean retention time of Cr (P = 0.02). Aspirin increased SAA (P = 0.04) and tended to increase LBP (P = 0.09) in serum but did not affect any other serum inflammatory marker (P ≥ 0.19). Aspirin tended to increase jejunal CLDN-1 mRNA expression (P = 0.10) but did not affect the mRNA expression of other genes regulating tight junction function (P ≥ 0.20). Results from this study indicate that aspirin disrupts the GIT barrier function in beef cattle and has a potential as a model in GIT permeability research.

Project description:BackgroundMesenchymal stem cells (MSCs) have been shown to alleviate acute lung injury (ALI) and induce the production of regulatory dendritic cells (DCregs), but the potential link between these two cell types remains unclear. The goal of this study was to investigate the effect and mechanism of MSC-induced regulatory dendritic cells in ALI mice.Material/methodsIn vivo experiments, C57BL/6 wild-type male mice were sacrificed at different times after intratracheal injection of LPS to observe changes in lung DC maturation and pathological damage. MSCs, DCregs or/and carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled DCs were administered to the mice by tail vein, and flow cytometry was performed to measure the phenotype of lung DCs and T cells. Lung injury was estimated by the lung wet weight/body weight ratio and histopathological analysis. In vitro, Western blotting or flow cytometry was used to detect the expression of Notch ligand or receptor in MSCs or DCs after coculture or LPS stimulation. Finally, in vivo and in vitro, we used the Notch signaling inhibitor DAPT to verify the effect of the Notch pathway on MSC-induced DCregs and their pulmonary protection.ResultsWe showed significant accumulation and maturation of lung DCs 2 h after intratracheal injection of LPS, which were positively correlated with the lung pathological injury score. MSC treatment alleviated ALI lung injury, accompanied by a decrease in the number and maturity of classical DCs in the lungs. CFSE-labeled DCs migrated to the lungs of ALI mice more than those of the normal group, and the elimination of CFSE-labeled DCs in the blood was slower. MSCs inhibited the migration of CFSE-labeled DCs to the lung and promoted their elimination in the blood. DCregs, which are obtained by contact coculture of mDCs with MSCs, expressed reduced levels of MHCII, CD86, CD40 and increased levels of PD-L1, and had a reduced ability to stimulate lymphocyte proliferation and activation (expression of CD44 and CD69). mDCs expressing Notch2 significantly increased after coculture with MSCs or rhJagged1, and MSCs expressed more Jagged1 after LPS stimulation. After stimulation of mDCs with recombinant Jagged1, DCs with low expression of MHCII, CD86 and CD40 were also induced, and the effects of both rhJagged1 and MSCs on DCs were blocked by the Notch inhibitor DAPT. Intra-airway DAPT reversed the inhibitory effect of mesenchymal stem cells on DC recruitment to the lungs and its maturation.ConclusionsOur results suggested that the recruitment and maturation of lung DCs is an important process in early ALI, MSCs attenuate LPS-induced ALI by inducing the production of DCregs by activating Notch signaling.

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Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract.

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Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract.

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