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The article discusses a study which examines the effect of dietary melibiose (6-o-α-D-galactopyranosyl-D-glucose) on T-helper (Th) cell responses induced by an orally fed antigen in ovalbumin-specific T cell receptor transgenic mice. Dietary melibiose significantly decreased the Th2 type responses, shown by a significant decrease in the interleukin-4 production and T cell proliferative response induced by sensitization from the oral administration of ovalbumin.

To investigate the mechanisms inducing food-sensitive intestinal inflammation, we focused on the OVA23-3 mouse, a transgenic mouse strain expressing a T cell receptor that recognizes ovalbumin (OVA). Mice administered an egg-white (EW) diet containing OVA showed a trend of loose feces and significant weight loss. Histology of the jejunum showed severe inflammation with villous atrophy. Thus, we studied the role of T cells and intestinal microflora in the development of the inflammation. Severe villous disruption was observed in sections of the jejunum from OVA23-3 mice and RAG-2 gene-deficient OVA23-3 mice fed with EW-diet. Further, a larger number of T cells was found in the lamina propria of the jejunum of EW-diet fed OVA23-3 mice, RAG-2 gene-deficient mice and germfree OVA23-3 mice compared with those of control-diet fed mice. However, severe inflammation was not detected in the jejunum of germfree OVA23-3 mice. CD4^{+} T cells from the MLN of EW-diet fed OVA23-3 mice showed a Th2 cytokine secretion profile. These observations have thus clarified that antigen-specific Th2 cells play important roles in the development of intestinal inflammation. Although the presence of indigenous bacteria was not essential for the inflammation, T cells could mediate a more severe inflammatory response in their presence. [ABSTRACT FROM AUTHOR]

Reports on a study which reveals that antigen feeding increases frequency and antigen-specific proliferation ability of intraepithelial CD4[sup +] T cells in alphabeta T cell receptor transgenic mice. Changes in the population of IEL in response to orally administered Ag; Changes in Ag-specific reactivity of IEL in response to orally administered Ag; Proliferative response of CD4[sup +] and CD4[sup -] IEL sorted by MACS.

We examined intracellular signaling of hyporesponsive CD4 T cells induced by continuous feeding with high-dose antigen in a TCR transgenic mouse system. The results demonstrated a selective impairment in their TCR-induced calcium/NFAT-signaling pathway. Proteomic analysis revealed caspase activation in these cells, which resulted in cleavage of GADS. Further analysis of the TCR-signaling complex showed that GADS-LAT-SLP-76-associated PLC-γ1 was decreased in both phosphorylation and association. Thus, as a consequence of caspase activation, orally tolerant CD4 T cells could not form normal TCR signaling complexes associated with GADS and showed downregulated PLC-γ1 activation, which resulted in impairment of TCR-induced calcium signaling. [ABSTRACT FROM AUTHOR]

Abstract: Colonization of the gut by commensal bacteria modulates the induction of oral tolerance and allergy. However, how these intestinal bacteria modulate antigen-specific T cell responses induced by oral antigens remains unclear. In order to investigate this, we used germ-free (GF) ovalbumin (OVA)-specific T cell receptor transgenic (OVA23-3) mice. Conventional (CV) or GF mice were administered an OVA-containing diet. Cytokine production by CD4+ cells from spleen (SP), mesenteric lymph nodes (MLN) and Peyer''s patches (PP) was evaluated by ELISA, as was the peripheral antibody titer. T cell phenotype was assessed by flow cytometry. CD4+ cells from the SP and MLN of CV and GF mice fed an OVA diet for 3 weeks produced significantly less IL-2 than the corresponding cells from mice receiving a control diet, suggesting that oral tolerance could be induced at the T cell level in the systemic and intestinal immune systems of both bacterial condition of mice. However, we also observed that the T cell hyporesponsiveness induced by dietary antigen was delayed in the systemic immune tissues and was weaker in the intestinal immune tissues of the GF mice. Intestinal MLN and PP CD4+ T cells from these animals also produced lower levels of IL-10, had less activated/memory type CD45RBlow cells, and expressed lower levels of CTLA-4 but not Foxp3 compared to their CV counterparts. Furthermore, GF mice produced higher serum levels of OVA-specific antibodies than CV animals. CD40L expression by SP CD4+ cells from GF mice fed OVA was higher than that of CV mice. These results suggest that intestinal commensal bacteria promote T cell hyporesponsiveness and down-regulate serum antibody responses induced by dietary antigens through modulation of the intestinal and systemic T cell phenotype. [Copyright &y& Elsevier]

Abstract: Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to ingested antigens (Ag). Dendritic cells (DC) have been revealed as important immune regulators, however, the precise role of DC in oral tolerance induction remains unclear. We investigated the characteristics of DC in spleen, mesenteric lymph node (MLN), and Peyer''s patch (PP) after oral Ag administration in a TCR-transgenic mouse model. DC from PP and MLN of tolerized mice induced IL-10 production but not Foxp3 expression in cocultured T cells. IL-10 production was markedly increased after 5–7-day Ag administration especially in PP DC. On the other hand, IL-27 production was increased after 2–5-day Ag administration. CD11b+ DC, which increased after ingestion of Ag, prominently expressed IL-10 and IL-27 compared with CD11b− DC. These results suggest that IL-10 and IL-27 producing DC are increased by interaction with antigen specific T cells in PP, and these DC act as an inducer of IL-10 producing T cells in oral tolerance. [Copyright &y& Elsevier]

Abstract: Bifidobacterium is a dominant bacterial species among commensals in the human intestine and is thought to have probiotic immunomodulatory effects. In this study, we investigated the effect of the association with Bifidobacterium pseudocatenulatum JCM 7041 (Bp) on dietary ovalbumin (OVA)-specific immune responses using germ-free OVA-specific T cell receptor transgenic mice (OVA23-3 mice). We established germ-free OVA23-3 mice, and then associated with Bp (BIF group) or without (CONT group) and additionally associated with segmented filamentous bacteria (SFB) and clostridia in both groups. BIF and CONT mice were fed an egg-white diet containing OVA for 1 week. Cytokine production in response to OVA by cells of Peyer''s patches (PPs) and lamina propria (LP) from the small and large intestine was measured. Interferon (IFN)-γ and interleukin (IL)-6 production by PP cells from BIF group mice was lower than that of the CONT group. The proportion of PP cells expressing CD4+CD62Llow, an activated/memory T cell phenotype, was higher in BIF group mice than the CONT group. Furthermore, LP cells from the small intestine in Bp-associated mice showed a tendency to produce slightly lower IFN-γ and IL-6, while the cells from large intestine produced markedly higher IFN-γ, IL-5 and IL-6 than those in the CONT group. The pattern of cytokine production by PP in BIF animals was similar to those isolated from conventional mice. These results suggest that intestinal association with Bp might down-regulate excessive immune responses to dietary antigens of the small intestine but enhance those of the large intestine. [Copyright &y& Elsevier]

Abstract: Intraepithelial lymphocytes (IELs) are considered to drive immune surveillance of the epithelial layer to the mucosa, which is initially exposed to exogenous antigens. However, how IELs are activated by orally administered antigens remains unclear. To clarify this mechanism, we fed ovalbumin (OVA) to T cell receptor transgenic (TCR-Tg) mice with OVA-specific MHC class II-restricted TCR and found that the cytotoxic activity of IELs was increased against both NK and LAK target cells, but notably reduced after depleting CD8+ IELs. Cytoplasmic staining showed that the production of IFN-γ and IL-2 was increased in mice fed with OVA both in the supernatant of cultured IELs with immobilized anti-CD3mAb and in fresh CD4+ IELs. In contrast, the cytotoxic activity against NK and LAK target cells and the production of IL-2 and IFN-γ was decreased in splenic T cells from mice fed with OVA. However, when the splenic T cells from these mice were cultured with OVA and IL-2, IFN-γ production recovered. The decreased response demonstrated the clonal anergy of T cells. Furthermore, tumor growth was enhanced in TCR-Tg mice carrying an OVA-transfected counterpart A20 B cell lymphoma (OVA-A20) and fed with OVA. These results indicate that the oral administration of soluble antigens can activate CD4+ IELs in an antigen-specific manner but induces hyporesponsiveness in the spleen. In addition, Th1-type cytokines produced by activated CD4+ IEL might provide a bystander effect on the cytotoxic activity of IELs. [Copyright &y& Elsevier]