TNF-α-Dependent and -Independent Maturation of Dendritic Cells and Recruited CD11cintCD11b+ Cells during Oral Salmonella Infection

Maturation of dendritic cells (DC) is crucial for their ability to induce adaptive immunity. Although several mediators of DC maturation have been found, their contributions to DC maturation during infection are poorly understood. In this study we show that murine conventional (CD11c(high)) DC up-regulate costimulatory molecules in a subset-specific manner after oral Salmonella infection. Although both CD8alpha+ and CD8alpha- subsets increase CD86 expression, CD40 was preferentially up-regulated on CD8alpha+ DC, and CD80 was preferentially increased on CD8alpha- DC. In addition, high levels of CD80 and CD86 were found on CD11c(int)CD11b+ cells that accumulated in infected organs. Costimulatory molecules were simultaneously induced on CD11c(high) and CD11c(int)CD11b+ cells in Peyer's patches, mesenteric lymph nodes and spleen 5 days after infection despite different kinetics of peak bacterial burden in these organs. Up-regulation of costimulatory molecules occurred on all DC within the respective subset. Moreover, <1% of CD11c-expressing cells associated with Salmonella expressing enhanced GFP in vivo. Thus, DC maturation did not depend on bacterial uptake. Rather, infection-induced up-regulation of CD80, CD86, and CD40 on CD11c-expressing cells of mesenteric lymph nodes was dependent on TNFR type I (TNFRI) signaling. Although indirect up-regulation of costimulatory molecules on DC and CD11c(int)CD11b+ cells was TNFRI dependent, cells directly associated with Salmonella were able to mature independently of TNFRI signaling. Thus, Salmonella-induced TNF-alpha is an important mediator of indirect DC maturation during infection, whereas a TNF-alpha-independent maturation pathway contributes to direct maturation of bacteria-associated DC.