Mesenteric Lymph Nodes Confine Dendritic Cell-Mediated Dissemination of Salmonella enterica Serovar Typhimurium and Limit Systemic Disease in Mice

Abstract

ABSTRACT In humans with typhoid fever or in mouse strains susceptible to Salmonella enterica serovar Typhimurium ( S . Typhimurium) infection, bacteria gain access to extraintestinal tissues, causing severe systemic disease. Here we show that in the gut-draining mesenteric lymph nodes (MLN), the majority of S. Typhimurium-carrying cells show dendritic-cell (DC) morphology and express the DC marker CD11c, indicating that S . Typhimurium bacteria are transported to the MLN by migratory DCs. In vivo FLT-3L-induced expansion of DCs, as well as stimulation of DC migration by Toll-like receptor agonists, results in increased numbers of S . Typhimurium bacteria reaching the MLN. Conversely, genetically impaired DC migration in chemokine receptor CCR7-deficient mice reduces the number of S . Typhimurium bacteria reaching the MLN. This indicates that transport of S . Typhimurium from the intestine into the MLN is limited by the number of migratory DCs carrying S . Typhimurium bacteria. In contrast, modulation of DC migration does not affect the number of S . Typhimurium bacteria reaching systemic tissues, indicating that DC-bound transport of S . Typhimurium does not substantially contribute to systemic S . Typhimurium infection. Surgical removal of the MLN results in increased numbers of S . Typhimurium bacteria reaching systemic sites early after infection, thereby rendering otherwise resistant mice susceptible to fatal systemic disease development. This suggests that the MLN provide a vital barrier shielding systemic compartments from DC-mediated dissemination of S . Typhimurium. Thus, confinement of S . Typhimurium in gut-associated lymphoid tissue and MLN delays massive extraintestinal dissemination and at the same time allows for the establishment of protective adaptive immune responses.