Gut regulatory T cells mediate immunological tolerance in Salmonella-infected superspreader hosts.

Abstract Salmonella Typhimurium is an enteric pathogen that causes gastroenteritis in humans and Typhoid fever-like symptoms in mice. Our lab has shown that oral infection of 129X1/SvJ mice with Salmonella Typhimurium results in ~25% of mice becoming persistent high-shedders (>10 8CFU/g feces). Because these mice can transmit infection to a naïve host, we refer to them as super-spreaders (SS). Unexpectedly, SS mice are asymptomatic despite a persistent high-pathogen burden in the gut. We hypothesized that SS mice are disease resistant due to a gut-specific immune state that facilitates homeostasis between host and pathogen. To examine this, we performed extensive immuno-phenotyping of SS mice, which revealed a distinct type-1 immune state in the gut. We found that IFNγ producing effector CD4 T cells were the dominant population to accumulate in SS guts. Additionally, a population of Tbet+ Tregs were found only in the gut of SS mice, suggesting these cells may enable the SS asymptomatic state. Accordingly, specific ablation of Tregs resulted in a dramatic weight loss, gut inflammation, and a compromised epithelial barrier in SS mice. Bacterial burden was unchanged in Treg depleted mice, demonstrating that morbidity was not caused by Salmonella burden but likely due to immune pathology. Indeed, depletion of effector CD4+ T cells in Treg-deficient SS mice reversed this morbidity, confirming the disease state was directly caused by immune pathology. These results demonstrate that in SS mice Tregs play an essential tolerogenic role maintaining intestinal homeostasis. We are currently investigating the immunological mechanisms triggering this effect and whether this new immune-adapted state may impact infections with other enteric pathogens.