Bacillus subtilis-specific poly- -glutamic acid regulates development pathways of naive CD4+ T cells through antigen-presenting cell-dependent and -independent mechanisms

ArticleinInternational Immunology 21(8):977-90 · July 2009with7 Reads
DOI: 10.1093/intimm/dxp065 · Source: PubMed
Abstract
Peripheral naive CD4+ T cells selectively differentiate to type 1 Th, type 2 Th and IL-17-producing Th (Th17) cells, depending on the priming conditions. Since these subsets develop antagonistically to each other to elicit subset-specific adaptive immune responses, balance between these subsets can regulate the susceptibility to diverse immune diseases. The present study was undertaken to determine whether poly-γ-glutamic acid (γ-PGA), an edible and safe exopolymer that is generated by microorganisms such as Bacillus subtilis, could modulate the development pathways of Th subsets. The presence of γ-PGA during priming promoted the development of Th1 and Th17 cells but inhibited development of Th2 cells. γ-PGA up-regulated the expression of T-bet and ROR-γt, the master genes of Th1 and Th17 cells, respectively, whereas down-regulating the level of GATA-3, the master gene of Th2 cells. γ-PGA induced the expression of IL-12p40, CD80 and CD86 in dendritic cells (DC) and macrophages in a Toll-like receptor-4-dependent manner, and the effect of γ-PGA on Th1/Th2 development was dependent on the presence of antigen-presenting cells (APC). Furthermore, γ-PGA-stimulated DC favored the polarization of naive CD4+ T cells toward Th1 cells rather than Th2 cells. In contrast, γ-PGA affected Th17 cell development, regardless of the presence or absence of APC. Thus, these data demonstrate that γ-PGA has the potential to regulate the development pathways of naive CD4+ T cells through APC-dependent and -independent mechanisms and to be applicable to treating Th2-dominated diseases.
    • "Thus, we examined whether TLR4 is responsible for γPGA-mediated basophil reduction using TLR4-mutant C3H/HeJ and TLR4-sufficient C3H/HeN mice; as expected, γPGA treatment did not diminish the basophil population in C3H/HeJ mice unlike in C3H/HeN mice, suggesting that basophil reduction by γPGA is mediated through the TLR4 pathway (Fig 2D). Moreover, because DCs are known to initiate γPGA-mediated immune responses [17, 19], we analyzed the effect of γPGA on DCs. A single in vivo injection of γPGA up-regulated IL12 production and the expression of MHC class II molecules and costimulatory molecules such as CD86 in DCs (Fig 2E) . "
    [Show abstract] [Hide abstract] ABSTRACT: Recent studies have demonstrated that Bacillus subtilis-derived poly-gamma glutamic acid (γPGA) treatment suppresses the development of allergic diseases such as atopic dermatitis (AD). Although basophils, an innate immune cell, are known to play critical roles in allergic immune responses and repeated long-term administration of γPGA results in decreased splenic basophils in an AD murine model, the underlying mechanisms by which γPGA regulates basophil frequency remain unclear. To investigate how γPGA modulates basophils, we employed basophil-mediated Th2 induction in vivo model elicited by the allergen papain protease. Repeated injection of γPGA reduced the abundance of basophils and their production of IL4 in mice, consistent with our previous study using NC/Nga AD model mice. The depletion of basophils by a single injection of γPGA was dependent on the TLR4/DC/IL12 axis. CD1d-dependent Vα14 TCR invariant natural killer T (iNKT) cells are known to regulate a variety of immune responses, such as allergy. Because iNKT cell activation is highly sensitive to IL12 produced by DCs, we evaluated whether the effect of γPGA on basophils is mediated by iNKT cell activation. We found that in vivo γPGA treatment did not induce the reduction of basophils in iNKT cell-deficient CD1d KO mice, suggesting the critical role of iNKT cells in γPGA-mediated basophil depletion at the early time points. Furthermore, increased apoptotic basophil reduction triggered by iNKT cells upon γPGA stimulation was mainly attributed to Th1 cytokines such as IFNγ and TNFα, consequently resulting in inhibition of papain-induced Th2 differentiation via diminishing basophil-derived IL4. Taken together, our results clearly demonstrate that γPGA-induced iNKT cell polarization toward the Th1 phenotype induces apoptotic basophil depletion, leading to the suppression of Th2 immune responses. Thus, elucidation of the crosstalk between innate immune cells will contribute to the design and development of new therapeutics for Th2-mediated immune diseases such as AD.
    Full-text · Article · Apr 2016
    • "However, the immunomodulator poly-gamma glutamate (γ-PGA), which is produced by Bacillus subtilis chungkookjang, isolated from Chungkookjang, a traditional Korean fermented soybean food, is safe and edible [10] . Unlike other pathogenassociated molecular patterns, γ-PGA retains its watersoluble , biodegradable, and non-toxic properties [11, 12]. Previously, we identified this molecule as a potent inducer of the host immune response in in vivo tumor models [13, 14]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background The global outbreak of a novel swine-origin strain of the 2009 H1N1 influenza A virus and the sudden, worldwide increase in oseltamivir-resistant H1N1 influenza A viruses highlight the urgent need for novel antiviral therapy. Methods Here, we investigated the antiviral efficacy of poly-gamma glutamate (γ-PGA), a safe and edible biomaterial that is naturally synthesized by Bacillus subtilis, against A/Puerto Rico/8/1934 (PR8) and A/California/04/2009 (CA04) H1N1 influenza A virus infections in C57BL/6 mice. Results Intranasal administration of γ-PGA for 5 days post-infection improved survival, increased production of antiviral cytokines including interferon-beta (IFN-β) and interleukin-12 (IL-12), and enhanced activation of natural killer (NK) cells and influenza antigen-specific cytotoxic T lymphocytes (CTL) activity. Conclusions These results suggest that γ-PGA protects mice against H1N1 influenza A virus by enhancing antiviral immune responses.
    Full-text · Article · Oct 2015
    • "co-stimulatory molecules [5] . CD11c + splenic DCs and bone marrow-derived DCs express IL12p40, CD40, and CD86 in response to cPGA stimulation. "
    [Show abstract] [Hide abstract] ABSTRACT: Bacillus subtilis-derived poly-γ-glutamic acid (γPGA) stimulates dendritic cells (DCs) to produce IL12, leading to CD4+ T cell differentiation toward the Th1 phenotype, but DCs consist of heterogeneous subpopulations with a variety of immune functions. Among these, natural killer dendritic cells (NKDCs) play an important role in anti-tumor immune responses. Herein, we demonstrate the role of NKDCs in γPGA-meditated anti-tumor immune responses. NK1.1+ CD11c+ NKDCs were stimulated upon γPGA stimulation in vitro and in vivo to up-regulate lymphocyte activation markers, MHC class I and II, and co-stimulatory molecules. In particular, NKDCs were activated by γPGA to produce IFNγ and TNFα, like NK cells, as well as IL12, like DCs, implying that NKDCs have unique and multifunctional roles. Importantly, NKDCs stimulated by γPGA conferred stronger anti-tumor effects in mice and showed increased cytotoxicity against various tumor cell lines in vitro. In conclusion, NKDCs are one of the key players in anti-tumor immunity induced by γPGA.
    Full-text · Article · Dec 2013
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