| 1. |
- Tam, Miguel A., 1976, et al.
(författare)
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Early cellular responses to Salmonella infection: dendritic cells, monocytes, and more.
- 2008
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Ingår i: Immunological reviews. - 1600-065X. ; 225, s. 140-62
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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.
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| 2. |
- Marks, Ellen, 1982, et al.
(författare)
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The female lower genital tract is a privileged compartment with IL-10 producing dendritic cells and poor Th1 immunity following Chlamydia trachomatis infection.
- 2010
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Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- While a primary genital tract infection with C. trachomatis stimulates partial-protection against re-infection, it may also result in severe inflammation and tissue destruction. Here we have dissected whether functional compartments exist in the genital tract that restrict Th1-mediated protective immunity. Apart from the Th1-subset, little is known about the role of other CD4(+) T cell subsets in response to a genital tract chlamydial infection. Therefore, we investigated CD4(+) T cell subset differentiation in the genital tract using RT-PCR for expression of critical transcription factors and cytokines in the upper (UGT) and lower genital tract (LGT) of female C57BL/6 mice in response to C. trachomatis serovar D infection. We found that the Th1 subset dominated the UGT, as IFN-γ and T-bet mRNA expression were high, while GATA-3 was low following genital infection with C. trachomatis serovar D. By contrast, IL-10 and GATA-3 mRNA dominated the LGT, suggesting the presence of Th2 cells. These functional compartments also attracted regulatory T cells (Tregs) differently as increased FoxP3 mRNA expression was seen primarily in the UGT. Although IL-17A mRNA was somewhat up-regulated in the LGT, no significant change in RORγ-t mRNA expression was observed, suggesting no involvement of Th17 cells. The dichotomy between the LGT and UGT was maintained during infection by IL-10 because in IL-10-deficient mice the distinction between the two compartments was completely lost and a dramatic shift to the predominance of Th1 cells in the LGT occurred. Unexpectedly, the major source of IL-10 was CD11c(+) CD11b(+) DC, probably creating an anti-inflammatory privileged site in the LGT.
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| 3. |
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| 4. |
- Tam, Miguel A., 1976, et al.
(författare)
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Differential expansion, activation and effector functions of conventional and plasmacytoid dendritic cells in mouse tissues transiently infected with Listeria monocytogenes.
- 2006
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Ingår i: Cellular microbiology. - : Hindawi Limited. - 1462-5814 .- 1462-5822. ; 8:7, s. 1172-87
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DC) are crucial in generating immunity to infection. Here we characterize changes in DC in terms of number, activation and effector functions, focusing on conventional DC (cDC) and plasmacytoid DC (pDC), in Listeria-infected mice. Kinetic studies showed a subset- and tissue-specific expansion of cDC and upregulation of CD80 and CD86 on splenic and mesenteric lymph node (MLN) cDC after intragastric infection. Expansion of pDC was more prolonged than cDC, and pDC upregulated CD86 and MHC-II, but not CD80, in both the spleen and MLN. cDC were an important source of IL-12 but not TNF-alpha during infection, while pDC made neither of these cytokines. Instead other CD11c(int) cells produced these cytokines. Using five-colour flow cytometry and double intracellular cytokine staining, we detected phenotypically similar CD11c(int)CD11b(+)Gr1(+) cells with distinct capacities to produce TNF-alpha/IL-12 or TNF-alpha/iNOS (inducible nitric oxide synthase) in Listeria-infected tissues. IL-12p70 was also produced by sorted CD11c(hi) and CD11c(int)CD11b(+)Gr1(+) cells. Furthermore, production of TNF-alpha, iNOS and IL-12 was differentially dependent on cellular localization of the bacteria. Cytosol-restricted bacteria induced TNF-alpha and iNOS-producing cells, albeit at lower frequency than wild-type bacteria. In contrast, IL-12 was induced only with wild-type bacteria. These data provide new insight into the relative abundance and function of distinct CD11c-expressing populations during the early stage of Listeria infection.
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| 5. |
- Tam, Miguel A., 1976
(författare)
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Mechanisms of dendritic cell maturation induced by intracellular bacteria infection
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dendritic cells (DCs) are essential for the development of an immune response against pathogens such as Listeria monocytogenes and Salmonella typhimurium. This is mostly because of their unique capacity to stimulate naïve T cells. Before DCs become potent antigen presenting cells, they undergo a maturation process that enables them to efficiently stimulate naïve T cells. This process includes upregulation of costimulatory molecules such as CD80 and CD86 and production of cytokines. However, the pathway by which DCs mature can influence their capacity to induce effector functions in T cells. Thus, the aim of this thesis was to investigate the maturation and function of DCs during intracellular bacteria infection and its impact on T cell stimulation. Conventional DCs expanded in number and upregulated costimulatory molecules in a subset- and tissue-specific manner after oral Listeria infection. Moreover, plasmacytoid DCs also expanded and upregulated CD86 and MHC-II although showing no tissue specificity. Conventional DCs produced significant amounts of IL-12. In addition, a complex CD11c-expressing population was identified, stratified in several subsets defined by production of TNF-?, iNOS and IL-12 alone or in combination. The production of these molecules was dependent on the subcellular compartment where Listeria was localized. Upregulation of CD80 and CD86 in DCs during orally acquired Listeria was differentially dependent on MyD88 and IFN-??R. However, when the bacteria reached the blood stream directly, alternative pathways different than those mediated by MyD88 and IFN-??R induced upregulation of costimulatory molecules. Remarkably, IFN-??R-/- mice expressed higher levels of CD80 and CD86, which translated into stronger naïve T cell stimulation. However, despite the significance of IFN-??R in the early anti-Listeria response, it had little impact in the development of memory T cells. Similar to Listeria, expression of costimulatory molecules during Salmonella infection was only partially dependent on MyD88 and IFN-??R. Expression of CD80 was controlled by MyD88, whereas the MyD88-independent upregulation of CD86 was supported by IFN-?/?. Furthermore, Salmonella-associated DCs upregulated CD86 and CD80 to some extent even in the simultaneous absence of both MyD88 and IFN-??R. However, DCs that matured by direct contact with the bacteria, but in the absence of these two factors, were less competent at stimulating naïve T cells than their wild type counterpart due to a decreased capacity to process bacteria-derived antigens. Taken together, these studies expand our understanding of DC function during bacterial infection. In addition, the identification of factors involved in DC maturation addressed here can help to design more efficient approaches in the future to eliminate bacterial infections.
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| 6. |
- Tam, Miguel A., 1976, et al.
(författare)
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MyD88 and IFN-alphabeta differentially control maturation of bystander but not Salmonella-associated dendritic cells or CD11cintCD11b+ cells during infection.
- 2008
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Ingår i: Cellular microbiology. - : Hindawi Limited. - 1462-5822 .- 1462-5814. ; 10:7, s. 1517-29
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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.
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| 7. |
- Tam, Miguel A., 1976, et al.
(författare)
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MyD88 and interferon-alpha/beta are differentially required for dendritic cell maturation but dispensable for development of protective memory against Listeria.
- 2009
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Ingår i: Immunology. - : Wiley. - 1365-2567 .- 0019-2805. ; 128:3, s. 429-38
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Tidskriftsartikel (refereegranskat)abstract
- Signalling pathways mediated by MyD88 are important for sensing Toll-like receptor (TLR) ligands and directing an immune response. However, the influence of MyD88-derived cytokines and interferon (IFN)-alpha/beta, the latter being made by both MyD88-dependent and -independent pathways, in phenotypic and functional dendritic cell (DC) maturation during infection is poorly understood. Here we investigate the contribution of MyD88-dependent and -independent pathways to DC maturation, CD8 T-cell activation and the generation of protective memory against Listeria monocytogenes. We show that neither MyD88 deficiency alone nor MyD88/IFN-alphabetaR double deficiency alters Listeria-induced costimulatory molecule up-regulation on DCs in vivo. In contrast, DCs from infected IFN-alphabetaR(-/-) mice had higher CD80 and CD86 expression than wild-type DCs. We then examined the function of DCs matured in infected knockout mice. We found that DCs from Listeria-infected MyD88(-/-) and MyD88(-/-) IFN-alphabetaR(-/-) mice induced little or no IFN-gamma by CD8 T cells, respectively. In contrast, DCs from infected IFN-alphabetaR(-/-) mice had a greater capacity to induce IFN-gamma compared with DCs from infected wild-type mice. When the CD8 T-cell memory response was analysed, infected MyD88(-/-) and MyD88(-/- )IFN-alphabetaR(-/-) mice were found to have fewer bacteria-specific memory CD8 T cells than wild-type mice. However, the fraction of bacteria-specific CD8 T cells making IFN-gamma was similar in all mouse strains, and MyD88(-/-) and MyD88(-/- )IFN-alphabetaR(-/-) mice survived lethal challenge. Together the data suggest an inhibitory effect of IFN-alpha/beta on functional DC maturation during Listeria infection and reveal overlapping roles of MyD88-induced cytokines and IFN-alpha/beta in DC maturation and protective anti-Listeria immunity.
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| 8. |
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| 9. |
- Tam, Miguel A., 1976, et al.
(författare)
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Plasmacytoid dendritic cells mature independently of MyD88 and IFN-alpha beta R in response to Listeria and stimulate CD8 T cells
- 2011
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Ingår i: IMMUNOLOGY LETTERS. - 0165-2478. ; 138:2, s. 104-112
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Plasmacytoid dendritic cells (pDCs) are a subpopulation of dendritic cells specialized in the production of IFN-alpha/beta, particularly during viral infections. In this way pDCs directly impact antiviral immunity and influence T cell activation. However, despite their role as modulators of the immune response, their function as antigen-presenting cells (APCs) remains poorly understood. Indeed, their capacity as APCs during bacterial infections is unexplored. Here we investigate the importance of MyD88 and IFN-alpha/beta in upregulating costimulatory molecules on pDCs during Listeria infection and their impact on activation of naive CD8 T cells. We show that pDCs efficiently upregulate CD80 and CD86 during systemic Listeria infection, yet express lower levels of these molecules than conventional dendritic cells (cDCs). Furthermore, pDCs are able to stimulate CD8 T cell proliferation and IFN-gamma production, although less efficiently than cDCs. Despite these differences, the influence of MyD88 and IFN-alpha/beta on CD80 and CD86 expression on pDCs and cDCs is similar. Thus, our data show for the first time the potential of pDCs to activate CD8 T cells in response to a bacterial infection. (C) 2011 Elsevier B.V. All rights reserved.
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