Peripheral naive CD4(+) T cells selectively differentiate to type 1 T(h), type 2 T(h) and IL-17-producing T(h) (T(h)17) 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-gamma-glutamic acid (gamma-PGA), an edible and safe exopolymer that is generated by microorganisms such as Bacillus subtilis, could modulate the development pathways of T(h) subsets. The presence of gamma-PGA during priming promoted the development of T(h)1 and T(h)17 cells but inhibited development of T(h)2 cells. gamma-PGA up-regulated the expression of T-bet and ROR-gammat, the master genes of T(h)1 and T(h)17 cells, respectively, whereas down-regulating the level of GATA-3, the master gene of T(h)2 cells. gamma-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 gamma-PGA on T(h)1/T(h)2 development was dependent on the presence of antigen-presenting cells (APC). Furthermore, gamma-PGA-stimulated DC favored the polarization of naive CD4(+) T cells toward T(h)1 cells rather than T(h)2 cells. In contrast, gamma-PGA affected T(h)17 cell development, regardless of the presence or absence of APC. Thus, these data demonstrate that gamma-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 T(h)2-dominated diseases.
"Our recent study has shown that low-molecular-weight (50 kDa) cPGA induces Th1 differentiation through antigen presenting cell (APC)-dependent mechanisms. cPGA activates DCs and macrophages to produce IL12p40 and co-stimulatory molecules . 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.
Biochemical and Biophysical Research Communications 12/2013; 443(2). DOI:10.1016/j.bbrc.2013.11.097. · 2.30 Impact Factor
"Nanoparticles, composed of í µí»¾-PGA and L-phenylalanine ethylester, served as an adjuvant, which was able to activate dendritic cells (DC) and enhance adaptive immune responses against antigens carried by the nanoparticles . Bacillus-derived í µí»¾-PGA regulates the developmental pathways of naive CD4 T cells through antigen-presenting cell-dependent and -independent mechanisms . Moreover , recently, Lee et al. reported that Bacillus-derived í µí»¾-PGA attenuates allergic airway inflammation through a toll-like receptor-4-dependent pathway in a murine model of asthma . "
[Show abstract][Hide abstract] ABSTRACT: Poly- γ -glutamic acid ( γ -PGA), naturally secreted from various strains of Bacillus, has anti-inflammatory activity. In inflammatory bowel disease (IBD), inflammation is promoted and sustained by angiogenesis; however, the role played by γ -PGA in this condition is unclear. Therefore, we evaluated γ -PGA effects on angiogenesis and inflammation in a dextran sulfate sodium- (DSS-) induced mouse colitis model. Experimental colitis was induced in male C57BL/6 mice by administering 3% DSS. Disease activity index (DAI), histopathological scores, microvascular density, myeloperoxidase activity, and VEGF-A and VEGFR2 expression were compared among control mice, DSS-treated mice, and mice receiving 3% DSS along with γ -PGA at 50 mg/kg body weight per day or 3% DSS with γ -PGA at 200 mg/kg body weight per day. We found that γ -PGA significantly attenuated weight loss, DAI, and colon shortening. γ -PGA also significantly reduced histopathological evidence of injury. Moreover, γ -PGA significantly attenuated DSS-induced blood vessel densities. Furthermore, γ -PGA attenuated DSS-induced expression of VEGF-A and its receptor, VEGFR2. In addition, γ -PGA treatment led to reduced recruitment of leukocytes to the inflamed colon. Therefore, our results indicate that γ -PGA has potential application in conditions marked by inflammatory-driven angiogenesis and mucosal inflammation.
Mediators of Inflammation 12/2013; 2013(25-26):982383. DOI:10.1155/2013/982383 · 3.24 Impact Factor
"Taken together, this cytokine reporter mouse model should prove invaluable, not only in understanding how activation of innate immune cells such as DCs regulates adaptive immune responses including infectious diseases and tumor immunity but also in evaluating novel compounds that can act as adjuvants to promote more effective immune responses [64,66]. We have recently used the IL-12 p40 reporter system to demonstrate that poly-γ-glutamic acid, an edible and safe exopolymer generated by microorganisms such as Bacillus subtilis, can modulate T helper cell differentiation by activation of DCs . "
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DCs) are antigen presenting cells that are characterized by a potent capacity to initiate immune responses. DCs comprise several subsets with distinct phenotypes. After sensing any danger(s) to the host via their innate immune receptors such as Toll-like receptors, DCs become mature and subsequently present antigens to CD4(+) T cells. Since DCs possess the intrinsic capacity to polarize CD4(+) helper cells, it is critical to understand the immunological roles of DCs for clinical applications. Here, we review the different DC subsets, their danger-sensing receptors and immunological functions. Furthermore, the cytokine reporter mouse model for studying DC activation is introduced.
Mark C Dessing, Jesper Kers, Jeffrey Damman, Henri G D Leuvenink, Harry van Goor, Jan-Luuk Hillebrands, Bouke G Hepkema, Harold Snieder, Jacob van den Born, Martin H de Borst, Stephan J L Bakker, Gerjan J Navis, Rutger J Ploeg, Sandrine Florquin, Marc Seelen, Jaklien C Leemans
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