Maturation of dendritic cells derived from type 1 diabetes-susceptible NOD mice is differentially regulated by two strains of generally regarded as safe (GRAS) Lactobacillus

Abstract

Abstract Although commensal bacteria have been implicated in type 1 diabetes (T1D), specific mechanistic insight is limited. We hypothesized that specific strains of commensal bacteria can modulate the diabetogenic peripheral T cell effector repertoire (PTER) through differential dendritic cell (DC) maturation. To test this, we assessed the presence of an IL17+ PTER and compared the microbial profiles present within female non-obese diabetic (NOD) mice, which spontaneously develop TID, and non-obese resistant (NOR) mice, which are resistant to T1D. We also assessed changes in DC maturation mediated by generally regarded as safe (GRAS) Lactobacillus johnsonii N6.2 (LjN6.2) versus Lactobacillus reuteri TD1 (LrTD1), which were previously shown to inhibit and accelerate T1D, respectively, in bio-breeding diabetes-prone (BBDP) rats. We found that NOR mice possessed a distinct Th17 bias and higher CD11c+MHCII+ DCs frequencies within lymph nodes and pancreas when compared to NOD mice. In vitro, LjN6.2 induced production of IL-6, IL-10, and TGF-b, previously shown to prime protective IL17+ T lymphocytes. Additionally, LjN6.2 promoted dendritic cell expression of the tolerogenic signaling molecules SOCS1, B7-H4, and PD-L1. In contrast, LrTD1 promoted production of proinflammatory cytokines, IL-12 and IL-23, which share a common p40 subunit. Together these data suggest that certain bacterial strains may enhance tolerance mechanisms and, thereby, contribute toward an environment that might protect against T1D, whereas bacterial strains such as LrTD1 may act as an “inducing” environmental factor by enhancing IL-12 production. Hence, these results emphasize a need to elucidate immunological mechanisms mediated by GRAS bacteria.