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

Abstract

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 (CD11chigh) DC up-regulate costimulatory molecules in a subset-specific manner after oral Salmonella infection. Although both CD8α+ and CD8α− subsets increase CD86 expression, CD40 was preferentially up-regulated on CD8α+ DC, and CD80 was preferentially increased on CD8α− DC. In addition, high levels of CD80 and CD86 were found on CD11cintCD11b+ cells that accumulated in infected organs. Costimulatory molecules were simultaneously induced on CD11chigh and CD11cintCD11b+ 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 CD11cintCD11b+ cells was TNFRI dependent, cells directly associated with Salmonella were able to mature independently of TNFRI signaling. Thus, Salmonella-induced TNF-α is an important mediator of indirect DC maturation during infection, whereas a TNF-α-independent maturation pathway contributes to direct maturation of bacteria-associated DC.

Anatomic location defines antigen presentation by dendritic cells to T cells in response to intravenous soluble antigens

“…The unique Ag-presenting capacity of the CD8a -CD11b + DC subset in MLN described in the present study may be another complexity of DC in GALT. Moreover, this DC subset in MLN has been shown to take up Salmonella after oral infection with this microbe [15]. Although a recent study demonstrated that CD8a -CD11b -DC in Peyer's patches take up viral Ag from apoptotic cells and cross-present it to cognate T cells, this population did not appear to be a major cross-presenting APC in the present study [20].…”

“…Although CD8a -CD11b + DC, CD8a + CD11b -DC and B220 + plasmacytoid DC (PDC) are present in every secondary lymphoid tissue, there is an additional double-negative population (CD8a -CD11b -) in LN that is not dominant in spleen and a double-positive subset (CD8a + CD11b + ) that represents a major population only in LN other than mesenteric LN (MLN) [5,6]. A number of experimental models, most performed with splenic DC, suggest that each subset serves a unique role in the immune system [2,[6][7][8][9][10][11][12][13][14][15][16]. Moreover, CD8a + and CD8a -splenic DC have different gene-expression profiles, a finding that strongly supports a functional difference between these two subsets [17].…”

Monocyte and neutrophil recruitment during oral Salmonella infection is driven by MyD88‐derived chemokines

“…Tissue lysates and serum were prepared as described previously [4]. Concentrations of CCL2, CXCL9 and CXCL2 in PP and MLN extracts, serum samples and sorted cell populations were determined using either the Opt EIA Elisa kit (BD) or mouse cytokine bead array (CBA) kit (BD Biosciences) for CCL2.…”

“…Murine monocytes in the blood are a heterogeneous population and have been divided into two main subsets based on whether they are present in steady state or recruited under inflammatory conditions [1]. Inflammatory Gr-1 hi CCR2 hi CX 3 CR1 low monocytes, which have also been called TipDC upon entering a tissue, are a source of molecules important in controlling bacterial infection, particularly iNOS and TNF-a [2][3][4].…”

“…Murine monocytes in the blood are a heterogeneous population and have been divided into two main subsets based on whether they are present in steady state or recruited under inflammatory conditions [1]. Inflammatory Gr-1 hi CCR2 hi CX 3 CR1 low monocytes, which have also been called TipDC upon entering a tissue, are a source of molecules important in controlling bacterial infection, particularly iNOS and TNF-a [2][3][4].Salmonella enterica serovar Typhimurium (S. typhimurium) is a Gram-negative facultative intracellular bacterium that infects via the oral route. Orally acquired Salmonella exits the gut lumen primarily by crossing the follicle-associated epithelium overlying Peyer's patches (PP) via M cells (reviewed in [5]).…”