| 1. |
|
|
| 2. |
- Sundquist, Malin, 1978
(författare)
-
Dendritic cell maturation and death during Salmonella infection. Role of pro-inflammatory cytokines and MyD88
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The costimulatory molecules CD80 and CD86 are required for the ability of dendritic cells (DC) to induce both tolerance and immunity. This thesis investigates the control of CD80/CD86 upregulation in vivo on DC during Salmonella infection. After oral Salmonella infection, DC in Peyer?s patches (PP), mesenteric lymph nodes (MLN) and spleen upregulated costimulatory molecules almost simultaneously despite differential seeding of these organs with bacteria. Costimulatory molecules were also induced on TNF/iNOS-producing CD11cintCD11b+ DC that accumulated in infected organs. The CD11cintCD11b+ DC were efficient at bacterial uptake but, in contrast to conventional DC, failed to process and present Salmonella Ag on MHC-II. Using different gene-deficient mice, the pathways controlling CD80/86 upregulation on DC during Salmonella infection were dissected. Upregulation of CD80 was strictly dependent on the Toll-like receptor adaptor MyD88, whereas upregulation of CD86 was mediated by both MyD88-dependent and -independent factors. The pro-inflammatory cytokine TNF was identified as one MyD88-dependent factor required for optimal upregulation of CD80/86 in the MLN. In the absence of MyD88, upregulation of CD86 was mediated by type I interferons. However, the contribution of type I interferons to CD86 upregulation in wild type mice is only marginal, since mice lacking the type I interferon receptor (IFN-??R) showed no major defects in CD80/86 upregulation. Despite the abrogated upregulation of CD80/86 on DC of TNFR1-/-, MyD88-/- or MyD88-/-IFN-??R-/- mice, DC directly associated with bacteria upregulated costimulatory molecules independently of these factors. Pro-inflammatory signaling not only upregulated costimulatory molecules on DC during Salmonella infection, but also mediated DC death. Thus, MyD88-dependent production of TNF induced DC death in Salmonella-infected mice. CD8?+ DC were most susceptible to infection-induced cell death as assessed directly ex vivo by Annexin-V and 7AAD staining, whereas recruited CD11cintCD11b+ DC were completely resistant. Thus, the inflammatory environment imprints a distinct pattern of costimulatory molecules on DC, with MyD88-dependent factors controlling the upregulation of CD80. However, MyD88-dependent factors also induce DC death during Salmonella infection, which is likely to have a negative impact on anti-bacterial immunity.
|
|
| 3. |
- Sundquist, Malin, 1978, et al.
(författare)
-
Salmonella induces death of CD8alpha(+) dendritic cells but not CD11c(int)CD11b(+) inflammatory cells in vivo via MyD88 and TNFR1.
- 2009
-
Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 85:2, s. 225-34
-
Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs), whose lifespan influences their ability to stimulate the immune system, are potent APCs that are critical for initiating immunity. Here, we show that oral infection with Salmonella enterica serovar Typhimurium induces death of DCs in the gut-draining lymph nodes. Although CD8alpha(+) DCs were sensitive to Salmonella-induced death, CD8alpha(-) DCs and in particular recruited CD11c(int)CD11b(+) inflammatory cells, were resistant. Infecting mice deficient for MyD88 revealed that Salmonella-induced death of CD8alpha(+) DCs was dependent on this adaptor for TLR signaling. In addition, CD8alpha(+) DCs in infected, TNFR1-deficient mice were resistant to Salmonella-induced death. These data, combined with the strict MyD88-dependent production of TNF in Salmonella-infected mice, suggest that MyD88-dependent TNF mediates DC death. As recruited CD11c(int)CD11b(+) cells were resistant to Salmonella-induced death, they could compensate for the infection-induced loss of DCs if they function as APCs. However, in contrast to DCs, CD11c(int)CD11b(+) cells could not present the model antigen OVA expressed in Salmonella to OVA-specific CD4 T cells. These results show that Salmonella induces DC death after oral infection via MyD88 and TNFR1, which could have a negative impact on the initiation of antibacterial immunity.
|
|
| 4. |
- Sundquist, Malin, 1978, et al.
(författare)
-
TNF-alpha-dependent and -independent maturation of dendritic cells and recruited CD11c(int)CD11b+ Cells during oral Salmonella infection.
- 2005
-
Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 175:5, s. 3287-98
-
Tidskriftsartikel (refereegranskat)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 (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.
|
|
| 5. |
- Tam, Miguel A., 1976, et al.
(författare)
-
Early cellular responses to Salmonella infection: dendritic cells, monocytes, and more.
- 2008
-
Ingår i: Immunological reviews. - 1600-065X. ; 225, s. 140-62
-
Forskningsöversikt (refereegranskat)abstract
- SUMMARY: Dendritic cells (DCs), monocytes, macrophages, and neutrophils are myeloid-derived phagocytes critical to controlling bacterial infections, and these cells have complementary functions to ensure host survival. Recent data have shed light on the dynamics and function of myeloid cells at the early stage of infection. In particular, murine infection models with Salmonella enterica serovar Typhimurium have been useful for understanding the host response required to develop immunity to systemic salmonellosis. This review summarizes the early cellular responses in the intestinal lymphoid tissues to Salmonella and discusses Peyer's patch-dependent and -independent penetration of bacteria through the intestinal epithelium. Once Salmonella accesses host tissue, phagocytes respond by recruitment, redistribution, and activation in intestinal tissues. Recruited monocytes are specialized in controlling bacterial replication by producing anti-microbial molecules but are poor antigen-presenting cells. In contrast, DCs undergo maturation by direct (bacteria-mediated) and indirect (cytokine-mediated) pathways in vivo to optimize their antigen presentation capacity, and directly matured DCs have unique mechanisms to ensure T-cell stimulation. Toll-like receptor signaling is critical to DC maturation and myeloid cell recruitment during Salmonella infection, and the role of myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways as well as proinflammatory cytokines and type 1 interferons in these processes are discussed.
|
|
| 6. |
- Tam, Miguel A., 1976, et al.
(författare)
-
MyD88 and IFN-alphabeta differentially control maturation of bystander but not Salmonella-associated dendritic cells or CD11cintCD11b+ cells during infection.
- 2008
-
Ingår i: Cellular microbiology. - : Hindawi Limited. - 1462-5822 .- 1462-5814. ; 10:7, s. 1517-29
-
Tidskriftsartikel (refereegranskat)abstract
- The interface between dendritic cells (DCs) and T cells is critical to elicit effective immunity against pathogens. The maturation state of DCs determines the quality of the interaction and governs the type of response. DCs can be matured directly through activating Toll-like receptors (TLRs) or indirectly by cytokines. We explore the role of the TLR adaptor MyD88 on DC maturation during Salmonella infection. Using Salmonella expressing GFP, we also examine the phenotype and function of bacteria-associated DCs matured in the absence of bacteria-mediated TLR signalling. MyD88 was required for upregulation of CD80 on DCs during infection, whereas CD86 and CD40 were upregulated independently of MyD88, although requiring a higher bacterial burden in the MLN. MyD88-independent upregulation was mediated by IFN-alphabeta produced during infection. In infected MyD88(-/-)IFN-alphabetaR(-/-) mice, which lack most bacteria-driven TLR signalling, indirect DC maturation was abolished. In contrast, DCs containing Salmonella upregulated co-stimulatory molecules independently of MyD88 and IFN-alphabeta, revealing a pathway of phenotypic maturation active in infected DCs. However, despite high co-stimulatory molecule expression, Salmonella-containing DCs from MyD88(-/-) or MyD88(-/-)IFN-alphabetaR(-/-) mice had a compromised capacity to activate T cells. Thus, bacterial stimulation of TLRs influences DC function at multiple levels that modulates their capacity to direct antibacterial immunity.
|
|
