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