| 1. |
- Hultkrantz, Susanne, 1977, et al.
(author)
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Induction of antigen-specific regulatory T cells in the liver-draining celiac lymph node following oral antigen administration.
- 2005
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In: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 116:3, s. 362-72
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Journal article (peer-reviewed)abstract
- Regulatory T cells are induced by oral administration of an antigen, but the physiological requirements and localization of the inductive sites are largely unknown. Using an adoptive transfer system of cells transgenic for ovalbumin T-cell receptor (OVA TCR tg), we found that antigen-specific CD4+ T cells were activated in the liver-draining celiac lymph node (CLN) shortly after ovalbumin feeding, and that a significantly higher proportion of the T cells in the CLN developed into the putative regulatory phenotype [co-expressing CD25 with the glucocortico-induced tumour necrosis factor (TNF) receptor family related gene (GITR), cytotoxic T-lymphocyte antigen (CTLA)-4 and CD103] than in Peyer's patches, the mesenteric and peripheral lymph nodes and the spleen. In addition, a particularly high level of expression of CD103 on the OVA-specific T cells in the CLN may favour homing to the epithelium of the intestine. While equally suppressive, OVA tg T cells isolated from the CLN of OVA-fed DO11.10 mice were less dependent on transforming growth factor (TGF)-beta for suppression than cells isolated from the peripheral and mesenteric lymph nodes, which indicates the involvement of an additional suppressive mechanism. The expression of FoxP3 was not up-regulated in any of the lymph node compartments studied. Our phenotypic and functional findings suggest that the induction of regulatory T cells in the CLN may be relevant in the control of the immune response to dietary antigens.
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| 2. |
- Lönnqvist, Anna, 1980, et al.
(author)
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Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy.
- 2009
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In: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 39:2, s. 447-56
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Journal article (peer-reviewed)abstract
- The hygiene hypothesis suggests that lack of microbial stimulation in early infancy may lead to allergy, but it has been difficult to identify particular protective microbial exposures. We have observed that infants colonised in the first week(s) of life with Staphylococcus aureus have lower risk of developing food allergy. As many S. aureus strains produce superantigens with T-cell stimulating properties, we here investigate whether neonatal mucosal exposure to superantigen could influence the capacity to develop oral tolerance and reduce sensitisation and allergy. BALB/c mice were exposed to staphylococcal enterotoxin A (SEA) as neonates and fed with OVA as adults, prior to sensitisation and i.n. OVA challenge. Our results show that SEA pre-treated mice are more efficiently tolerised by OVA feeding, as shown by lower lung-cell infiltration and antigen-specific IgE response in the SEA pre-treated mice, compared with sham-treated mice. This was not due to deletion or anergy of lymphocytes by SEA treatment, because the SEA pre-treated mice that were fed with PBS showed similar inflammatory response as the sham-treated PBS-fed mice. Our results suggest that strong T-cell activation in infancy conditions the mucosal immune system and promotes development of oral tolerance.
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| 3. |
- Östman, Sofia M, 1974, et al.
(author)
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Impaired regulatory T cell function in germ-free mice.
- 2006
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In: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 36:9, s. 2336-46
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Journal article (peer-reviewed)abstract
- Regulatory T cells (Treg) are crucial for the maintenance of tolerance to auto-antigens and harmless exogenous antigens. Here, we studied the role of the commensal microbiota for the development and function of Treg. CD4+CD25+ T cells were obtained from peripheral lymph nodes (PLN) and mesenteric lymph nodes (MLN) of germ-free (GF) and conventional (conv) NMRI mice and tested for phenotype and functional suppressive capacity. CD4+CD25+ T cells from GF mice showed a lower relative gene expression of fork head box p3 gene (Foxp3) and were not as potent suppressors in vitro as CD4+CD25+ T cells from conv animals. Intracellular staining for Foxp3 and CTLA-4 revealed proportional and regional differences in putative Treg subsets between conv and GF mice. Fewer of the CD4+CD25+ T cells in GF MLN expressed Foxp3 and CTLA-4, while the expression of these markers was similar amongst the CD4+CD25+ T cells in PLN of conv and GF mice. The largest difference between conv and GF Treg was observed in the liver draining celiac lymph node, where GF mice had fewer putative Treg as compared to conv mice. We propose that the presence of a microbial flora favors the development of a fully functional Treg population.
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| 4. |
- Östman, Sofia M, 1974
(author)
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Oral tolerance mechanisms and the role of the microbiota
- 2005
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Doctoral thesis (other academic/artistic)abstract
- The hygiene hypothesis state that microbial stimulation is necessary to fully activate and mature the immune system and to sustain tolerance mechanisms. Oral tolerance maintains immune homeostasis in the gut and prevents adverse reactions towards the comensal flora and Ags from the food and thus protects from development of allergies and inflammatory bowel diseases (IBD). The mechanisms underlying oral tolerance remain elusive but it has become clear that regulatory T cells are important mediators of oral tolerance although, little is known on how and where these regulatory T cells are induced. In order to induce oral tolerance the Ag (Ag) must be processed in the intestine. Ags present in the lumen are sampled by intestinal epithelial cells (IECs) and enter an endosomal/ lysosomal pathway that leads to loading of Ag peptides on major histocompability class class II molecules (MHCII), present on vesicular structures that are released from the IECs. Our research group was the first to identify that these vesicular structures named tolerosomes are present in serum after oral Ag administration. Tolerosomes isolated from serum shortly after a feed of Ag induce Ag specific tolerance when transferred into naive recipients. Mature intestines with MHCII expression in the IECs are necessary for development of oral tolerance and this maturation requires the presence of a comensal flora. The aim of this thesis was to study mechanisms of oral tolerance with focus on the generation of tolerosomes and what role the microbiota play in this process, and to investigate the influence of a comensal flora on the maturation of the immune system including generation of regulatory T cells. We found that oral administration of ovalbumin (OVA) result in activation of Ag specific T cells in the gut associated lymphoid tissue (GALT) as well as at peripheral lymphoid sites, including the lymph nodes draining the liver i.e. celiac lymph nodes (CLN). The proportion of Ag-specific cells with regulatory T cells were highest in CLN and that suggests that CLN could be an important site during development of oral tolerance. In addition, co-administration of Cholera toxin and OVA, preserved oral tolerance in the fed mice and lead to an increase of T cells with regulatory T cell phenotype, especially in the CLN. We confirmed, that tolerosomes can be generated in a mouse system and show that the ability to generate tolerosomes is dependent on expression of MHCII in the IECs and furthermore that the function of tolerosomes is restricted by their MHC haplotype. Tolerosomes induce Ag specific T cells activation, both in vivo and in vitro and show phenotypical similarities with in vitro generated exosomes, derived from cultured IECs. Germ free (GF) mice are unable to generate tolerosomes and neither colonization with Escherichia coli or Lactobacilli, could restore this dysfunction or induce expression of MHCII in the IECs of the former GF mice. We also demonstrate that GF mice in general have a less developed immune system with malfunctioning regulatory T cells and reduced levels of the suppressive cytokine IL-10. In conclusion, these results agree with the hygiene hypothesis that suggests that the microbiota play a crucial role for maturation of the immune system and that microbes are essential for the proper function of the tolerance mechanisms that protects us from adverse reactions to harmless environmental Ags.
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| 5. |
- Östman, Sofia M, 1974, et al.
(author)
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Tolerosome-induced oral tolerance is MHC dependent.
- 2005
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In: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 116:4, s. 464-76
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Journal article (peer-reviewed)abstract
- Oral administration of a protein antigen generates a serum factor that induces tolerance when transferred into naïve recipients. This serum factor has been described in rats as consisting of exosome-like structures or tolerosomes, which express major histocompatibility complex class II molecules (MHCII) and mediate antigen-specific tolerance. In this study, we investigated the functions of serum-derived tolerosomes both in vivo and in vitro. Tolerosomes were purified from the 100,000 g pellet fraction of serum from ovalbumin (OVA)-fed mice. When transferred into naïve recipient mice, the tolerosomes mediated OVA-specific tolerance. We also found that tolerosomes from OVA-fed mice induced the activation of OVA-specific T cells both in vivo and in vitro. The inoculation of severe combined immunodeficiency (SCID) mice with an interferon-gamma-producing cell line normalized the expression of MHCII in the intestinal epithelial cells and restored their ability to generate tolerosomes. Syngeneic but not allogeneic transfer of tolerosomes from OVA-fed donors induced tolerance in the recipients. Our results show that tolerosomes can be isolated from mouse serum, that tolerosome-induced oral tolerance requires MHCII expression in intestinal epithelial cells, and that tolerosomes are functional only in syngeneic recipients.
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