Peripheral naive CD4⁺ T cells selectively differentiate to type 1 T_h, type 2 T_h and IL-17-producing T_h (T_h17) 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--glutamic acid (-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 -PGA during priming promoted the development of T_h1 and T_h17 cells but inhibited development of T_h2 cells. -PGA up-regulated the expression of T-bet and ROR-t, the master genes of T_h1 and T_h17 cells, respectively, whereas down-regulating the level of GATA-3, the master gene of T_h2 cells. -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 -PGA on T_h1/T_h2 development was dependent on the presence of antigen-presenting cells (APC). Furthermore, -PGA-stimulated DC favored the polarization of naive CD4⁺ T cells toward T_h1 cells rather than T_h2 cells. In contrast, -PGA affected T_h17 cell development, regardless of the presence or absence of APC. Thus, these data demonstrate that -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_h2-dominated diseases.

High-density lipoproteins (HDLs) protect pancreatic β-cells against apoptosis. This property might relate to the increased risk to develop diabetes in patients with low HDL blood levels. However, the mechanisms by which HDLs protect β-cells are poorly characterized. Here we used a transcriptomic approach to identify genes differentially modulated by HDLs in β-cells subjected to apoptotic stimuli. The transcript encoding 4E-binding protein (4E-BP)1 was up-regulated by serum starvation, and HDLs blocked this increase. 4E-BP1 inhibits cap-dependent translation in its non- or hypophosphorylated state but it loses this ability when hyperphosphorylated. At the protein level, 4E-BP1 was also up-regulated in response to starvation and IL-1β, and this was blunted by HDLs. Whereas an ectopic increase of 4E-BP1 expression induced β-cell death, silencing 4E-BP1 increase with short hairpin RNAs inhibited the apoptotic-inducing capacities of starvation. HDLs can therefore protect β-cells by blocking 4E-BP1 protein expression, but this is not the sole protective mechanism activated by HDLs. Indeed, HDLs blocked apoptosis induced by endoplasmic reticulum stress with no associated decrease in total 4E-BP1 induction. Although, HDLs favored the phosphorylation, and hence the inactivation of 4E-BP1 in these conditions, this appeared not to be required for HDL protection. Our results indicate that HDLs can protect β-cells through modulation of 4E-BP1 depending on the type of stress stimuli.