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Introduction: The intestinal immune system plays a pivotal role in the induction of immune responses against food. In the case of T cell response, dendritic cells (DCs) are especially important. However, the regulation of immune responses to food by intestinal DCs has been poorly described. In this study, we analyzed the effect of Lactococcus lactis subsp. cremoris YRC3780, a lactic acid bacterial strain isolated from kefir, a traditional fermented milk product, on the immune responses induced by antigen presentation by intestinal DCs to T cells as well as the mechanism of action of these immunomodulatory effects. It has been shown that L. cremoris YRC3780 ameliorates the symptoms of pollinosis in both animal and human studies., Methods: CD11c + cells from mesenteric lymph nodes (MLNs) of BALB/c mice were cultured as MLN DCs with L. cremoris YRC3780 and expression of genes inducing regulatory T cells (Tregs) was examined by qPCR. In addition, MLN DCs were cocultured with CD4 + T cells from DO11.10 transgenic mice expressing an ovalbumin (OVA)-specific TCR and the OVA antigen peptide and L. cremoris YRC3780. Induction of Tregs was examined by flow cytometry, gene expression was analyzed by DNA microarray and qPCR, and the production of cytokines was measured by ELISA. MLN DCs from TLR2-deficient mice and components of L. cremoris YRC3780 were used to examine the recognition of YRC3780 by MLN DCs., Results: L. cremoris YRC3780 enhanced the expression of genes involved in Treg induction in MLN DCs and induced Foxp3 + CD4 + T cells in an MLN DC and CD4 + T-cell co-culture system. The effect on MLN DCs was likely mediated by receptors other than TLR2. Together with microarray analyses of CD4 + T cell gene expression and cytokine ELISA, it was demonstrated that L. cremoris YRC3780 promoted the induction of Th1 and Tregs, and regulated the balance of Th1/Th2 and Treg/Th17 cells involving multiple genes via the antigen-presentation of MLN DCs., Discussion: Our findings provide insights into the modulation of intestinal immune responses mediated by DCs and the antiallergic effects of lactic acid bacteria., Competing Interests: Authors IF and KU were employed by the company Yotsuba Milk Products Co., Ltd. Author SH received a grant from Yotsuba Milk Products Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Nakagawa, Gu, Mizobuchi, Kodera, Takano, Wang, Fujioka, Uchida, Nakajima-Adachi and Hachimura.)

A decline in immune function with aging has been reported. Regulatory T cell (Treg) induction is known to decrease with age, and elucidating the underlying mechanism is important for preventing age-related diseases due to age-related chronic inflammation. In the intestine, dendritic cells (DCs) play an important role in inducing Tregs specific to oral antigens, and they efficiently induce Tregs via production of retinoic acid (RA), a vitamin A metabolite, catalyzed by the enzyme retinaldehyde dehydrogenase 2 (RALDH2). We have previously reported that in the mesenteric lymph node (MLN), a secondary lymphoid tissue in which immune responses to oral antigens are induced, four DC subsets express different levels of CD11b, CD103, and PD-L1, and we have reported that the CD11b - CD103 + PD-L1 high subset expresses the highest levels of the RALDH2 gene and induces Tregs in vitro . We examined Treg induction in young and aged mice using a Treg induction model by administering a food antigen, and we found that antigen-specific Treg induction was decreased in aged mice. We further investigated the MLN DCs, and a significant decrease in RALDH2 gene expression was observed in MLN DCs from aged mice. As factors, we found that the proportion of the CD11b - CD103 + PD-L1 high subset was decreased in aged mice compared with that in young mice and that RALDH enzyme activity was decreased in the CD11b - CD103 + PD-L1 high and CD11b + CD103 + PD-L1 high subsets. Furthermore, analysis of the methylation of the RALDH2 gene promoter region revealed that CpG motifs were more methylated in the MLN DCs of aged mice, suggesting that RALDH2 expression was suppressed by epigenetic changes. Finally, we found that RA treatment tended to increase Treg induction. These results suggest that the regulation of RA production may be involved in the age-related decrease in antigen-specific Treg induction., (Copyright © 2020 Takano, Kotaki, Park, Yoshida, Wakatsuki, Tanokura, Miyakawa, Takahashi, Nakajima-Adachi and Hachimura.)

Dendritic cells (DCs) in mesenteric lymph nodes (MLNs) induce Foxp3 + regulatory T cells to regulate immune responses to beneficial or non-harmful agents in the intestine, such as commensal bacteria and foods. Several studies in MLN DCs have revealed that the CD103 + DC subset highly induces regulatory T cells, and another study has reported that MLN DCs from programmed death ligand 1 (PD-L1) -deficient mice could not induce regulatory T cells. Hence, the present study investigated the expression of these molecules on MLN CD11c + cells. Four distinct subsets expressing CD103 and/or PD-L1 were identified, namely CD11b + CD103 + PD-L1 High , CD11b - CD103 + PD-L1 High , CD11b - CD103 + PD-L1 Low and CD11b + CD103 - PD-L1 Int . Among them, the CD11b - CD103 + PD-L1 High DC subset highly induced Foxp3 + T cells. This subset expressed Aldh1a2 and Itgb8 genes, which are involved in retinoic acid metabolism and transforming growth factor-β (TGF-β) activation, respectively. Exogenous TGF-β supplementation equalized the level of Foxp3 + T-cell induction by the four subsets whereas retinoic acid did not, which suggests that high ability to activate TGF-β is determinant for the high Foxp3 + T-cell induction by CD11b - CD103 + PD-L1 High DC subset. Finally, this subset exhibited a migratory DC phenotype and could take up and present orally administered antigens. Collectively, the MLN CD11b - CD103 + PD-L1 High DC subset probably takes up luminal antigens in the intestine, migrates to MLNs, and highly induces regulatory T cells through TGF-β activation., (© 2017 John Wiley & Sons Ltd.)

In the intestine, immune responses to commensal microbes should be regulated precisely. This regulation is achieved partly by dendritic cells (DCs), which recognize microbes through Toll-like receptors (TLRs). Although TLR responses have been intensely studied, cross-talk between individual TLRs remains unclear. The present study shows that TLR2 suppressed TLR9-induced Il12b gene expression and subsequent interleukin (IL)-12 and IL-23 production in DCs from Peyer's patch, a lymphoid tissue in the small intestine. The DCs expressed Il12b gene and produced IL-12 and IL-23 in response to TLR9 stimulation, and these responses were suppressed when the DCs were stimulated simultaneously with TLR2. The suppression was also observed in the non-intestinal DCs, such as spleen DCs and bone marrow-derived DCs. Peyer's patch DCs expressed Il12b gene also in response to TLR7 or CD40 stimulation, but these responses were not suppressed by simultaneous TLR2 stimulation. In addition, TLR9-induced Tnf and Il6 gene expression was not suppressed by TLR2. Furthermore, the supernatant of TLR2-stimulated DCs could not suppress TLR9-induced Il12b gene expression. These results suggest that TLR2 suppress TLR9-induced responses selectively, and this suppression is not mediated by secretory factors. The suppressive TLR cross-talk might play a certain role in preventing excess inflammatory responses to commensal microbes in the intestine and may have implications for the therapeutic strategies for intestinal inflammatory diseases, autoimmune diseases and cancer., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

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.

Beneficial effects of lactobacilli have been reported for patients with allergic diseases and intestinal disorders such as inflammatory bowel disease. However, it is not fully understood how such bacteria influence the immunologic response. For this purpose, we investigated the effect of Lactobacillus acidophilus strain L-92 (L-92) on antigen-stimulated T cell responses in vitro and in vivo. In vitro, L-92 decreased the proliferation of CD4(+) T cells stimulated with antigen, and also induced apoptosis of antigen-stimulated T cells. On the other hand, interferon (IFN)-gamma secretion from naïve T cells was increased while interleukin (IL)-4 secretion was decreased by L-92. Co-culture with L-92 induced apoptosis of differentiated Th1 and Th2 cells. The degree of apoptosis induction was higher in Th2 cells. Moreover, L-92 up-regulated the expression of B7-H1 and down-regulated that of B7-H2 on dendritic cells (DCs), and DCs exposed to L-92 also induced apoptosis of antigen-stimulated T cells. Finally, orally administered L-92 induced apoptosis of OVA-specific TCR Tg T cells. These results indicate that L-92 attenuates the CD4(+) T cell response by inducing DC-mediated apoptosis and that it might exert beneficial effects in patients with diseases resulting from a hyper-response of CD4(+) T cells.

Peyer's patch (PP) dendritic cells (DCs) have been shown to exhibit a distinct capacity to induce cytokine secretion from CD4(+) T cells compared with DCs in other lymphoid organs such as the spleen (SP). In this study, we investigated whether PP DCs are functionally different from DCs in the SP in their ability to induce Ab production from B cells. Compared with SP DCs, freshly isolated PP DCs induced higher levels of IgA secretion from naive B cells in DC-T cell-B cell coculture system in vitro. The IgA production induced by PP DCs was attenuated by neutralization of IL-6. In addition, the induction of IgA secretion by SP DCs, but not PP DCs, was further enhanced by the addition of exogenous IL-6. Finally, we demonstrated that only PP CD11b(+) DC subset secreted higher levels of IL-6 compared with other DC subsets in the PP and all SP DC populations, and that PP CD11b(+) DC induced naive B cells to produce higher levels of IgA compared with SP CD11b(+) DC. These results suggest a unique role of PP CD11b(+) DCs in enhancing IgA production from B cells via secretion of IL-6.

β-Glucans, glucose polymers that are the main constituents of the outer cell walls of micro-organisms such as fungi and yeast, are known to play an immunostimulatory role. We prepared β-glucan (β-(1-3),(1-6)-D-glucan) from an edible cultured fungus through fermentation techniques using a strain of Aureobasidium pullulans ADK-34. The purity of this β-glucan preparation ( AP- FBG) was demonstrated to be high through various instrumental analyses. We then examined the effects of AP- FBG on intestinal immune systems. We prepared Peyer's patch ( PP) cells and measured interleukin ( IL)-5, IL-6, and IgA production in culture media with AP- FBG. We found that both cytokines and IgA increased; furthermore, IL-6 secreted by PP dendritic cells ( PPDCs) cultured in the presence of AP- FBG significantly increased. We tested IgA production after oral administration of AP- FBG for 2 weeks and found that AP- FBG tended to promote the production of IgA in the small intestine. Interestingly, we observed a significant increase in IgA production in the small intestines of mice treated with cyclophosphamide ( CY; an immunosuppressant) after oral administration of AP- FBG diet compared with CY-treated and control diet mice. Production of IL-6 and IgA by PP cells and IL-6 production by PPDCs in AP- FBG-fed and CY-treated mice also increased. These results demonstrate that AP- FBG has the ability to activate PPDC and induce IL-6 production and IgA secretion in PP cells. These abilities were more clearly expressed when AP- FBG was orally administered in a CY-induced immunosuppressed condition. Therefore, AP- FBG may be a useful ingredient for preparing functional foods with immunomodulatory activities. [ABSTRACT FROM AUTHOR]