| 11. |
- 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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| 12. |
- Wenzel, Ulf Alexander, 1975, et al.
(författare)
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CD103(+)CD11b(+) Dendritic Cells Induce T(h)17 T Cells in Muc2-Deficient Mice with Extensively Spread Colitis
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria. The exact pathogenesis of UC remains unclear, but CD4(+) T cells reacting to commensal antigens appear to contribute to pathology. Given the unique capacity of dendritic cells (DCs) to activate naive T cells, colon DCs may activate pathogenic T cells and contribute to disease. Using Muc2(-/-) mice, which lack a functional mucus barrier and develop spontaneous colitis, we show that colitic animals have reduced colon CD103(+)CD11b(-) DCs and increased CD103(-)CD11b(+) phagocytes. Moreover, changes in colonic DC subsets and distinct cytokine patterns distinguish mice with distally localized colitis from mice with colitis spread proximally. Specifically, mice with proximally spread, but not distally contained, colitis have increased IL-1 beta, IL-6, IL-17, TNF alpha, and IFN gamma combined with decreased IL-10 in the distal colon. These individuals also have increased numbers of CD103(+)CD11b(+) DCs in the distal colon. CD103(+)CD11b(+) DCs isolated from colitic but not noncolitic mice induced robust differentiation of Th17 cells but not Th1 cells ex vivo. In contrast, CD103(-)CD11b(+) DCs from colitic Muc2(-/-) mice induced Th17 as well as Th1 differentiation. Thus, the local environment influences the capacity of intestinal DC subsets to induce T cell proliferation and differentiation, with CD103(+)CD11b(+) DCs inducing IL-17-producing T cells being a key feature of extensively spread colitis.
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| 13. |
- Wenzel, Ulf Alexander, 1975, et al.
(författare)
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Leishmania major parasite stage-dependent host cell invasion and immune evasion
- 2012
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Ingår i: FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 26, s. 29-39
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Tidskriftsartikel (refereegranskat)abstract
- Leishmania pathogenesis is primarily studied using the disease-inducing promastigote stage of Leishmania major. Despite many efforts, all attempts so far have failed to culture the disease-relevant multiplying amastigote stage of L. major. Here, we established a stably growing axenic L. major amastigote culture system that was characterized genetically, morphologically, and by stage-specific DsRed protein expression. We found parasite stage-specific disease development in resistant C57BL/6 mice. Human neutrophils, as first host cells for promastigotes, do not take up amastigotes. In human macrophages, we observed an amastigote-specific complement receptor 3-mediated, endocytotic entry mechanism, whereas promastigotes are taken up by complement receptor 1-mediated phagocytosis. Promastigote infection of macrophages induced the inflammatory mediators TNF, CCL3, and CCL4, whereas amastigote infection was silent and resulted in significantly increased parasite numbers: from 7.1 ± 1.4 (after 3 h) to 20.1 ± 7.9 parasites/cell (after 96 h). Our study identifies Leishmania stage-specific disease development, host cell preference, entry mechanism, and immune evasion. Since the amastigote stage is the disease-propagating form found in the infected mammalian host, the newly developed L. major axenic cultures will serve as an important tool in better understanding the amastigote-driven immune response in leishmaniasis. © FASEB.
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| 14. |
- Wenzel, Ulf Alexander, 1975, et al.
(författare)
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Spontaneous colitis in Muc2-deficient mice reflects clinical and cellular features of active ulcerative colitis.
- 2014
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- The colonic mucus layer plays a critical role in intestinal homeostasis by limiting contact between luminal bacteria and the mucosal immune system. A defective mucus barrier in animal models allows bacterial contact with the intestinal epithelium and results in spontaneous colitis. A defective mucus barrier is also a key feature of active ulcerative colitis (UC). Alterations in the immune compartment due to intestinal bacterial breach in mice lacking the colon mucus barrier have not been characterized and correlated to active UC.
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| 15. |
- Wenzel, Ulf Alexander, 1975, et al.
(författare)
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Synergy between CD40 and MyD88 does not influence host survival to Salmonella infection
- 2015
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies using purified toll-like receptor (TLR) ligands plus agonistic anti-CD40 antibodies showed that TLRs and CD40 can act synergistically on dendritic cells (DCs) to optimize T cell activation and Th1 differentiation. However, a synergistic effect of TLRs and CD40 during bacterial infection is not known. Here, we show that mice lacking the TLR adaptor MyD88 alone, or lacking both MyD88 and CD40 [double knockout (DKO) mice], are compromised in survival to Salmonella infection but have intact recruitment of neutrophils and inflammatory monocytes as well as unaltered abundance of DC subsets and DC activation in infected tissues. In contrast to infected wildtype and CD40(-/-) mice, both MyD88(-/-) mice and DKO mice lack detectable serum IFN-gamma and have elevated IL-10. A synergistic effect of TLRs and CD40 was revealed in co-culture experiments where 01-11 T cell proliferation was compromised when DKO DCs were pulsed with OVA protein and OVA(323-339) peptide, but not with heat-killed Salmonella expressing OVA (HKSOVA), relative to MyD88(-/-) DCs. By contrast, MyD88(-/-) or DKO DCs pulsed with any of the antigens had a similar ability to induce IFN-gamma that was lower than WT or CD40(-/-) DCs. DKO DCs pulsed with HKSOVA, but not with OVA or OVA(323-339), had increased IL-10 relative to MyD88(-/-) DCs. Finally, HKSHKSOVA-pulsed MyD88(-/-) and DKO DCs had similar and low induction of NF kappa B-dependent and independent genes upon co-culture with 01-11 cells. Overall, our data revealed that synergistic effects of CD40 and MyD88 do not influence host survival to Salmonella infection or serum levels of IFN-gamma or IL-10. However, synergistic effects of MyD88 and CD40 may be apparent on some (IL-10 production) but not all (01-11 proliferation and IFN-gamma production) DC functions and depend on the complexity of the antigen. Indeed, synergistic effects observed using purified ligands and well-defined antigens may not necessarily apply when complex antigens, such as live bacteria, challenge the immune system.
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