Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice.

ABSTRACT: Diarrheal diseases represent a major health burden in developing countries. Parenteral immunization typically does not induce efficient protection against enteropathogens because it does not stimulate migration of immune cells to the gut. Retinoic acid (RA) is critical for gut immunity, inducing upregulation of gut-homing receptors on activated T cells. In this study, we have demonstrated that RA can redirect immune responses elicited by s.c. vaccination of mice from skin-draining inguinal LNs (ingLNs) to the gut. When present during priming, RA induced robust upregulation of gut-homing receptors in ingLNs, imprinting gut-homing capacity on T cells. Concurrently, RA triggered the generation of gut-tropic IgA+ plasma cells in ingLNs and raised the levels of antigen-specific IgA in the intestinal lumen and blood. RA applied s.c. in vivo induced autonomous RA production in ingLN DCs, further driving efficient induction of gut-homing molecules on effector cells. Importantly, RA-supplemented s.c. immunization elicited a potent immune response in the small intestine that protected mice from cholera toxin–induced diarrhea and diminished bacterial loads in Peyer patches after oral infection with Salmonella. Thus, the use of RA as a gut-homing navigator represents a powerful tool to induce protective immunity in the intestine after s.c. immunization, offering what we believe to be a novel approach for vaccination against enteropathogens.

SUBMITTER: Hammerschmidt SI

PROVIDER: S-EPMC3223921 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Retinoic acid regulates the development of a gut-homing precursor for intestinal dendritic cells.

Project description:The vitamin A metabolite retinoic acid (RA) regulates intestinal immune responses through immunomodulatory actions on intestinal dendritic cells (DCs) and lymphocytes. Here, we show that RA also controls the generation of gut-tropic migratory DC precursors, referred to as pre-mucosal DCs (pre-?DCs). Pre-?DCs express the gut trafficking receptor ?4?7 and home preferentially to the intestines. They develop in the bone marrow (BM), can differentiate into CCR9? plasmacytoid DCs as well as conventional DCs (cDCs), but preferentially give rise to CD103? intestinal cDCs. Generation of pre-?DCs in vivo in the BM or in vitro is regulated by RA and RA receptor ? (RAR?) signaling. The frequency of pre-?DCs is reduced in vitamin A-deficient animals and in animals treated with RAR inhibitors. The results define a novel vitamin A-dependent, RA-regulated developmental sequence for DCs and identify a targeted precursor for CD103? cDCs in the gut.

| S-EPMC3612556 | biostudies-literature

Subcutaneous immunization with baculovirus surface-displayed hemagglutinin of pandemic H1N1 Influenza A virus induces protective immunity in mice.

Project description:The protective immunity of baculovirus displaying influenza virus hemagglutinin (BacHA) against influenza 2009 H1N1 virus infection in a murine model was investigated. The results showed that mice vaccinated with live BacHA or an inactive form of adjuvanted BacHA had enhanced specific antibody responses and induced protective immunity against 2009 H1N1 virus infection, suggesting the potential of baculovirus as a live or inactivated vaccine.

| S-EPMC3165240 | biostudies-literature

All-trans-retinoic acid imprints expression of the gut-homing marker ?4?7 while suppressing lymph node homing of dendritic cells.

Project description:Tissue-directed trafficking of dendritic cells (DCs) as natural adjuvants and/or direct vaccine carriers is highly attractive for the next generation of vaccines and immunotherapeutics. Since these types of studies would undoubtedly be first conducted using nonhuman primate models, we evaluated the ability of all-trans-retinoic acid (ATRA) to induce gut-homing ?4?7 expression on rhesus macaque plasmacytoid and myeloid DCs (pDCs and mDCs, respectively). Induction of ?4?7 occurred in both a time-dependent and a dose-dependent manner with up to 8-fold increases for mDCs and 2-fold increases for pDCs compared to medium controls. ATRA treatment was also specific in inducing ?4?7 expression, but not expression of another mucosal trafficking receptor, CCR9. Unexpectedly, upregulation of ?4?7 was associated with a concomitant downregulation of CD62L, a marker of lymph node homing, indicating an overall shift in the trafficking repertoire. These same phenomena occurred with ATRA treatment of human and chimpanzee DCs, suggesting a conserved mechanism among primates. Collectively, these data serve as a first evaluation for ex vivo modification of primate DC homing patterns that could later be used in reinfusion studies for the purposes of immunotherapeutics or mucosa-directed vaccines.

| S-EPMC3807207 | biostudies-literature

Retinoic acid receptor signaling levels and antigen dose regulate gut homing receptor expression on CD8+ T cells.

Project description:Recent studies have highlighted a central role for intestinal dendritic cells (DCs) and vitamin A metabolite retinoic acid (RA) in the generation of alpha4beta7(+) CCR9(+)"gut tropic" effector T cells. Here, using RA-responsive element reporter mice, we demonstrate that both splenic and mesenteric lymph node (MLN) DCs enhanced retinoic acid receptor (RAR) signaling in CD8(+) T cells; however, only a subset of MLN DCs, expressing the integrin alpha-chain CD103, induced an early RAR signal that is required for efficient CCR9 induction. MLN-primed CD8(+) T cells also received enhanced RAR-dependent signals compared with splenic-primed CD8(+) T cells in vivo. Further DC-mediated induction of gut homing receptors was inhibited at a high antigen dose without influencing RAR signaling events, and resulted in less efficient CD8(+) T-cell entry into the small intestinal mucosa. These results highlight a complex interplay between antigen dose and DC subset-induced RAR signaling events in the generation of tissue tropic effector T-cell subsets.

| S-EPMC6485487 | biostudies-literature

Gut homing receptors on CD8 T cells are retinoic acid dependent and not maintained by liver dendritic or stellate cells.

Project description:BACKGROUND & AIMS:Lymphocytes primed by intestinal dendritic cells (DC) express the gut-homing receptors CCR9 and alpha4beta7, which recognize CCL25 and mucosal addressin cell-adhesion molecule-1 in the intestine promoting the development of regional immunity. In mice, imprinting of CCR9 and alpha4beta7 is dependent on retinoic acid during T-cell activation. Tissue specificity is lost in primary sclerosing cholangitis (PSC), an extraintestinal manifestation of inflammatory bowel disease, when ectopic expression of mucosal addressin cell-adhesion molecule-1 and CCL25 in the liver promotes recruitment of CCR9+alpha4beta7+ T cells to the liver. We investigated the processes that control enterohepatic T-cell migration and whether the ability to imprint CCR9 and alpha4beta7 is restricted to intestinal DCs or can under some circumstances be acquired by hepatic DCs in diseases such as PSC. METHODS:Human and murine DCs from gut, liver, or portal lymph nodes and hepatic stellate cells were used to activate CD8 T cells. Imprinting of CCR9 and alpha4beta7 and functional migration responses were determined. Crossover activation protocols assessed plasticity of gut homing. RESULTS:Activation by gut DCs imprinted high levels of functional CCR9 and alpha4beta7 on naïve CD8 T cells, whereas hepatic DCs and stellate cells proved inferior. Imprinting was RA dependent and demonstrated plasticity. CONCLUSIONS:Imprinting and plasticity of gut-homing human CD8 T cells requires primary activation or reactivation by gut DCs and is retinoic acid dependent. The inability of liver DCs to imprint gut tropism implies that alpha4beta7+CCR9+ T cell that infiltrate the liver in PSC are primed in the gut.

| S-EPMC3201985 | biostudies-literature

BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid.

Project description:CCR9 and ?4?7 are the major trafficking receptors for lymphocyte migration to the gut, and their expression is induced during lymphocyte activation under the influence of retinoic acid (RA). We report here that BATF (basic leucine zipper transcription factor, ATF-like), an AP-1 protein family factor, is required for optimal expression of CCR9 and ?4?7 by T helper cells. BATF-deficient (knockout [KO]) mice had reduced numbers of effector T and regulatory T cells in the intestine. The intestinal T cells in BATF KO mice expressed CCR9 and ?4?7 at abnormally low levels compared with their wild-type (WT) counterparts, and BATF KO CD4(+) T cells failed to up-regulate the expression of CCR9 and ?4?7 to WT levels in response to RA. Defective binding of RAR? and histone acetylation at the regulatory regions of the CCR9 and Itg-?4 genes were observed in BATF KO T cells. As a result, BATF KO effector and FoxP3(+) T cells failed to populate the intestine, and neither population functioned normally in the induction and regulation of colitis. Our results establish BATF as a cellular factor required for normal expression of CCR9 and ?4?7 and for the homeostasis and effector functions of T cell populations in the intestine.

| S-EPMC3600908 | biostudies-other

Radiation and host retinoic acid signaling promote the induction of gut-homing donor T cells after allogeneic hematopoietic stem cell transplantation.

Project description:Intestinal graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although it has been well established that gut-tropic donor T cells expressing integrin α4β7 are required to cause intestinal damage, the factors that control the induction of this pathogenic T cell population remain to be identified. Retinoic acid (RA) plays an important role in inducing α4β7 expression on T cells. In this study, we showed that gene expression of retinaldehyde dehydrogenase, the key enzyme involved in RA biosynthesis, is significantly increased in the spleen and mesenteric lymph nodes (MLNs) of irradiated mice. In a C57BL/6-into-B6D2F1 allogeneic HSCT model, irradiation significantly increased the induction of α4β7+ -donor T cells in mesenteric lymph nodes and spleen. Furthermore, we found that the RA pathway modulates the ability of dendritic cells to imprint gut-homing specificity on alloreactive T cells. We also showed that host dendritic cell RA signaling influences GVHD risk. Our studies identified radiation and recipient RA signaling as 2 primary factors that dictate the magnitude of gut-homing donor T cell induction after allogeneic HSCT. Attenuating radiation-associated inflammation and modulating host RA signaling represent feasible strategies to mitigate intestinal GVHD by reducing gut-seeking pathogenic donor T cells.

| S-EPMC6918002 | biostudies-literature

Immunization with Toxoplasma gondii peroxiredoxin 1 induces protective immunity against toxoplasmosis in mice.

Project description:To develop a vaccine against Toxoplasma gondii, a vaccine antigen with immune-stimulating activity is required. In the present study, we investigated the immunogenicity and prophylactic potential of T. gondii peroxiredoxin 1 (TgPrx1). The TgPrx1 was detected in the ascitic fluid of mice 6 days postinfection, while specific antibody levels were low in the sera of chronically infected mice. Treatment of murine peritoneal macrophages with recombinant TgPrx1 triggered IL-12p40 and IL-6 production, but not IL-10 production. In response to TgPrx1, activation of NF-kB and IL-6 production were confirmed in mouse macrophage cell line (RAW 264.7). These results suggest the immune-stimulating potentials of TgPrx1. Immunization of mice with recombinant TgPrx1 stimulated specific antibody production (IgG1 and IgG2c). Moreover, spleen cell proliferation and interferon-gamma production significantly increased in the TgPrx1- sensitized cells from mice immunized with the same antigen. Immunization with TgPrx1 also increased mouse survival and decreased cerebral parasite burden against lethal T. gondii infection. Thus, our results suggest that TgPrx1 efficiently induces humoral and cellular immune responses and is useful as a new vaccine antigen against toxoplasmosis.

| S-EPMC5407612 | biostudies-literature

Immunization with truncated envelope protein of Zika virus induces protective immune response in mice.

Project description:The global spread of Zika virus (ZIKV) as well as its unexpected link to infant microcephaly have resulted in serious public health concerns. No antiviral drugs against ZIKV is currently available, and vaccine development is of high priority to prepare for potential ZIKV pandemic. In the present study, a truncated E protein with the N-terminal 90% region reserved (E90) from a contemporary ZIKV strain was cloned and expressed in Escherichia coli, purified by a Ni-NTA column, and characterized by Western blotting assays. Immunization with recombinant E90 induced robust ZIKV-specific humoral response in adult BALB/c mice. Passive transfer of the antisera from E90-immunized mice conferred full protection against lethal ZIKV challenge in a neonatal mice model. Our results indicate that recombinant ZIKV E90 described here represents as a promising ZIKV subunit vaccine that deserves further clinical development.

| S-EPMC5577204 | biostudies-literature

Mycobacterium bovis BCG immunization induces protective immunity against nine different Mycobacterium tuberculosis strains in mice.

Project description:Recent preclinical and epidemiologic studies have suggested that certain Mycobacterium tuberculosis genotypes (in particular, Beijing lineage strains) may be resistant to Mycobacterium bovis BCG vaccine-induced antituberculosis protective immunity. To investigate the strain specificity of BCG-induced protective responses in a murine model of pulmonary tuberculosis, C57BL/6 mice were vaccinated with BCG vaccine and then challenged 2 months later with one of nine M. tuberculosis isolates. Four of these strains were from the W-Beijing lineage (HN878, N4, NHN5, and ChS) while four were non-Beijing-type isolates (C913, CDC1551, NY669, and NY920). As a control, the WHO standard M. tuberculosis Erdman strain was evaluated in these vaccination/challenge experiments. To assess the protective responses evoked by BCG immunization, organ bacterial burdens and lung pathology were assessed in vaccinated and naïve mice at 4, 12, and 20 weeks postchallenge as well as during the day of infection. At 4 weeks after the aerosol challenge with each of these strains, significantly reduced bacterial growth in the lungs and spleens and significantly improved lung pathology were seen in all vaccinated animals compared to naïve controls. After 12 weeks, reduced organ bacterial burdens were detected in vaccinated animals infected with six of nine challenge strains. Although lung CFU values were lower in vaccinated mice for only three of nine groups at 20 weeks postchallenge, significantly decreased lung inflammation was seen in all immunized animals relative to controls at 20 weeks postchallenge. Taken together, these data demonstrate that BCG vaccination protects against infection with diverse M. tuberculosis strains in the mouse model of pulmonary tuberculosis and suggest that strain-specific resistance to BCG-induced protective immunity may be uncommon.

| S-EPMC2573355 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data