Gut bacteria modulate dendritic cell priming of diabetogenic T cell effector functions in a mouse model of autoimmune diabetes

Abstract

Abstract Increasing evidence implicates a contribution of the microbiome, within the gastrointestinal tract, in the initiation and progression of type 1 diabetes (T1D). Notably, our understanding of mechanisms whereby gut flora interaction with the host immune system can influence T1D pathogenesis remain poorly understood. Comparison of stool samples from the non-obese diabetic (NOD) mouse model of spontaneous T1D and non-obese resistant (NOR) mice revealed distinct bacterial flora communities present within the two strains correlated to a Th17 bias. Given that dendritic cells (DC) are critical in sampling luminal antigens and priming naïve T lymphocyte effector functions, we next interrogated the populations of CD11c+ DC within the lamina propria (LP) of NOD and NOR mice. Phenotypic characterization of LP DC revealed that NOR mice possessed more mature DC denoted by a higher frequency of CD11c+ MHCII+ cells and CD103+ CD86+ cells. We have previously shown that the oral administration of a gut bacterium Lactobaccillus johnsonii (LjN6.2), present in diabetes resistant rodents, was capable of conferring diabetes resistance to diabetes prone rodents while another strain Lactobacillus reuterii (LrTD1) had no effect. Notably, T1D resistance was correlated to a Th17 bias. Hence, we sought to investigate the influence of LjN6.2 on NOD and NOR DC in comparison to LrTD1 in vitro. We found that LjN6.2, but not LrTD1 mediated an increase in IL6 and IL10 cytokine production by DC. Together, these data suggest that gut bacteria have the important ability to shape the maturation and priming abilities of DC. These results could have critical implications regarding the ability of bacterial flora to regulate the generation of a diabetogenic immune repertoire.