| 1. |
- Jenkinson, William E., et al.
(författare)
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Chemokine receptor expression defines heterogeneity in the earliest thymic migrants
- 2007
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 37:8, s. 2090-2096
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Tidskriftsartikel (refereegranskat)abstract
- Chemokine signaling has been implicated in directing colonization of the fetal thymus by hematopoietic precursors. However, the patterns of expression of the chemokine receptors responsible for directing thymic colonization by the earliest thymic migrants remain unknown. We have identified heterogeneity within the earliest thymus seeding cells based on chemokine receptor expression. By analyzing the first wave of progenitors to colonize the thymus at E12 of gestation, we show that multiple chemokine receptors are expressed by T-lymphoid precursors present within perithymic mesenchyme, while expression of chemokine ligands is limited to CCL21, CCL25 and CXCL12, which are located in distinct epithelial and mesenchymal compartments of the thymic/parathyroid anlagen. Collectively, these results identify multiple populations of T-lymphoid precursors colonizing the fetal thymus and provide evidence for several potential pathways mediating migration of precursors into the embryonic thymus.
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| 2. |
- Svensson Frej, Marcus, et al.
(författare)
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Involvement of CCR9 at multiple stages of adult T lymphopoiesis.
- 2008
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 83:1, s. 156-164
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Tidskriftsartikel (refereegranskat)abstract
- The chemokine CCL25 is constitutively expressed in the thymus, and its receptor CCR9 is expressed on subsets of developing thymocytes. Nevertheless, the function of CCL25/CCR9 in adult thymopoiesis remains unclear. Here, we demonstrate that purified CCR9–/– hematopoietic stem cells are deficient in their ability to generate all major thymocyte subsets including double-negative 1 (DN1) cells in competitive transfers. CCR9–/– bone marrow contained normal numbers of lineage– Sca-1+c-kit+, common lymphoid progenitors, and lymphoid-primed multipotent progenitors (LMPP), and CCR9–/– LMPP showed similar T cell potential as their wild-type (WT) counterparts when cultured on OP9–{delta}-like 1 stromal cells. In contrast, early thymic progenitor and DN2 thymocyte numbers were reduced in the thymus of adult CCR9–/– mice. In fetal thymic organ cultures (FTOC), CCR9–/– DN1 cells were as efficient as WT DN1 cells in generating double-positive (DP) thymocytes; however, under competitive FTOC, CCR9–/– DP cell numbers were reduced significantly. Similarly, following intrathymic injection into sublethally irradiated recipients, CCR9–/– DN cells were out-competed by WT DN cells in generating DP thymocytes. Finally, in competitive reaggregation thymic organ cultures, CCR9–/– preselection DP thymocytes were disadvantaged significantly in their ability to generate CD4 single-positive (SP) thymocytes, a finding that correlated with a reduced ability to form TCR-MHC-dependent conjugates with thymic epithelial cells. Together, these results highlight a role for CCR9 at several stages of adult thymopoiesis: in hematopoietic progenitor seeding of the thymus, in the DN-DP thymocyte transition, and in the generation of CD4 SP thymocytes.
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| 3. |
- Agace, William
(författare)
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T-cell recruitment to the intestinal mucosa.
- 2008
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Ingår i: Trends in Immunology. - : Elsevier BV. - 1471-4981 .- 1471-4906. ; Oct 4., s. 514-522
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Tidskriftsartikel (refereegranskat)abstract
- The intestinal epithelium and underlying lamina propria contains large numbers of T cells that play an important role in maintaining intestinal homeostasis and defense against intestinal pathogens. Recent years have seen several significant advances in our understanding of the mechanisms regulating T-cell localization to the intestinal mucosa. For instance, we now know that the small intestine 'imprints' gut homing properties on T cells by inducing the expression of specific integrins and chemokine receptors. Further studies have identified distinct subsets of intestinal dendritic cells that use retinoic acid to generate both gut-tropic and regulatory T cells. As our understanding of the mechanisms regulating the generation of gut tropic T-cell populations evolves, the possibility of targeting these processes for mucosal vaccine development and treatment of intestinal immune pathology become more apparent.
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| 4. |
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| 5. |
- Andersson, David, et al.
(författare)
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Expression of Alkaline Sphingomyelinase in Yeast Cells and Anti-inflammatory Effects of the Expressed Enzyme in a Rat Colitis Model.
- 2009
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Ingår i: Digestive Diseases and Sciences. - : Springer Science and Business Media LLC. - 1573-2568 .- 0163-2116. ; 2008:Nov 7, s. 1440-1448
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Tidskriftsartikel (refereegranskat)abstract
- Alkaline sphingomyelinase (Alk-SMase) is a key enzyme in the intestinal tract for digestion of dietary sphingomyelin (SM), which generates lipid messengers with cell-cycle regulating effects. The enzyme is significantly decreased in ulcerative colitis and colon cancer. Based on this information, we wanted to investigate whether the enzyme had preventive effects against murine colitis. We report herein a method to express a biologically active Alk-SMase from Pichia pastoris yeast cells. By using the expressed enzyme to treat a rat colitis model induced by dextran sulfate sodium, we found that intrarectal instillation of Alk-SMase once daily for 1 week significantly reduced the inflammation score and protected the colonic epithelium from inflammatory destruction. We found a tendency for decreased tumor necrosis factor (TNF)-alpha expression in the Alk-SMase-treated group. This study, for the first time, provides a method to produce the enzyme and shows the potential applicability of the enzyme in the treatment of inflammatory bowel diseases.
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| 6. |
- Annacker, O, et al.
(författare)
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Essential role for CD103 in the T cell-mediated regulation of experimental colitis
- 2005
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 202:8, s. 1051-1061
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Tidskriftsartikel (refereegranskat)abstract
- The integrin CD103 is highly expressed at mucosal sites, but its role in mucosal immune regulation remains poorly understood. We have analyzed the functional role of CD103 in intestinal immune regulation using the T cell transfer model of colitis. Our results show no mandatory role for CD103 expression on T cells for either the development or CD4(+)CD25(+) regulatory T (T reg) cell-mediated control of colitis. However, wild-type CD4(+)CD25(+) T cells were unable to prevent colitis in immune-deficient recipients lacking CD103, demonstrating a nonredundant functional role for CD103 on host cells in T reg cell-mediated intestinal immune regulation. Non-T cell expression of CD103 is restricted primarily to CD11c(high) MHC class IIhigh dendritic cells (DCs). This DC population is present at a high frequency in the gut-associated lymphoid tissue and appears to mediate a distinct functional role. Thus, CD103(+) DCs, but not their CD103(-) counterparts, promoted expression of the gut-homing receptor CCR9 on T cells. Conversely, CD103(-) DCs promoted the differentiation of IFN-gamma-producing T cells. Collectively, these data suggest that CD103(+) and CD103(+) DCs represent functionally distinct subsets and that CD103 expression on DCs influences the balance between effector and regulatory T cell activity in the intestine.
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| 7. |
- Ericsson, Anna, et al.
(författare)
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Functional characterization of the CCL25 promoter in small intestinal epithelial cells suggests a regulatory role for caudal-related homeobox (Cdx) transcription factors
- 2006
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 176:6, s. 3642-3651
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Tidskriftsartikel (refereegranskat)abstract
- The chemokine CCL25 is selectively and constitutively expressed in the small intestinal epithelium and plays an important role in mediating lymphocyte recruitment to this site. In this study, we demonstrate that CCL25 expression in murine small intestinal epithelial cells is independent of signaling through the lymphotoxin 0 receptor and is not enhanced by inflammatory stimuli, pathways involved in driving the expression of most other chemokines. We define a transcriptional start site in the CCL25 gene and a region -141 to -5 proximal of exon 1 that is required for minimal promoter activity in the small intestinal epithelial cell lines, MODE-K and mICc12. These cell lines expressed far less CCL25 mRNA than freshly isolated small intestinal epithelial cells indicating that they are missing important factors driving CCL25 expression. The CCL25 promoter contained putative binding sites for,the intestinal epithelial-associated Caudal-related homeobox (Cdx) transcription factors Cdx-1 and Cdx-2, and small intestinal epithelial cells but not MODE-K and mICc12 cells expressed Cdx-1 and Cdx-2. EMSA analysis demonstrated that Cdx proteins were present in nuclear extracts from freshly isolated small intestinal epithelial cells but not in MODE-K or mICcl2 cells, and bound to putative Cdx sites within the CCL25 promoter. Finally, cotransfection of MODE-K cells with Cdx transcription factors significantly increased CCL25 promoter activity as well as endogenous CCL25 mRNA levels. Together these results demonstrate a unique pattern of regulation for CCL25 and suggest a role for Cdx proteins in regulating CCL25 transcription.
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| 8. |
- Jaensson Gyllenbäck, Elin, et al.
(författare)
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Small intestinal CD103(+) dendritic cells display unique functional properties that are conserved between mice and humans
- 2008
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205:9, s. 2139-2149
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Tidskriftsartikel (refereegranskat)abstract
- A functionally distinct subset of CD103(+) dendritic cells (DCs) has recently been identified in murine mesenteric lymph nodes (MLN) that induces enhanced FoxP3(+) T cell differentiation, retinoic acid receptor signaling, and gut-homing receptor (CCR9 and alpha 4 beta 7) expression in responding T cells. We show that this function is specific to small intestinal lamina propria (SI-LP) and MLN CD103(+) DCs. CD103(+) SI-LP DCs appeared to derive from circulating DC precursors that continually seed the SI- LP. BrdU pulse-chase experiments suggested that most CD103(+) DCs do not derive from a CD103(-) SI- LP DC intermediate. The majority of CD103(+) MLN DCs appear to represent a tissue- derived migratory population that plays a central role in presenting orally derived soluble antigen to CD8(+) and CD4(+) T cells. In contrast, most CD103(+) MLN DCs appear to derive from blood precursors, and these cells could proliferate within the MLN and present systemic soluble antigen. Critically, CD103(+) DCs with similar phenotype and functional properties were present in human MLN, and their selective ability to induce CCR9 was maintained by CD103(+) MLN DCs isolated from SB Crohn ' s patients. Thus, small intestinal CD103(+) DCs represent a potential novel target for regulating human intestinal infl ammatory responses.
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| 9. |
- Johansson, C, et al.
(författare)
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Differential expression of chemokine receptors on human IgA+ and IgG+ B cells.
- 2005
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Ingår i: Clinical and experimental immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 141:2, s. 279-87
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Tidskriftsartikel (refereegranskat)abstract
- Organ-specific lymphocyte homing is dependent on the expression of tissue-specific homing receptors and selected chemokine receptors. During the effector phase of an immune response, IgA and IgG antibody-secreting cells (ASC) are differently distributed in the body. Still, B cell expression of L-selectin and the mucosal homing receptor integrin alpha4beta7 is not related to the isotype produced, but only to the site of antigen encounter. In this study, we examined if differences in chemokine responsiveness between IgA+ and IgG+ B cells could explain their different tissue localization. Circulating CD19+ B cells were isolated and their expression of IgA, IgG, and selected chemokine receptors was determined by flow cytometry. Few Ig+ cells expressed CCR2, CCR3, or CCR9, and there was no difference in the expression of these receptors between IgA+ and IgG+ cells. In contrast, CCR4, CCR5, and CXCR3 was expressed on significantly more IgG+ than IgA+ cells. The function of chemokine receptors on memory B cells and ASC was then tested in the transwell system. IgG+ memory cells migrated to a higher extent than IgA+ cells towards the CXCR3 ligand CXCL11/I-TAC, while there was only a small migration towards the CCR4 ligand CCL17/TARC and the CCR9 ligand CCL25/TECK. ASC migrated poorly to all chemokines tested. In conclusion, this study shows that IgG+ and IgA+ memory B cells have a differential expression of the Th1 associated chemokine receptor CXCR3, as well as of CCR4 and CCR5. In contrast, none of the studied chemokine receptors was preferentially expressed by IgA+ cells.
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| 10. |
- Johansson Lindbom, Bengt, et al.
(författare)
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Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing.
- 2005
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 202:8, s. 1063-1073
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Tidskriftsartikel (refereegranskat)abstract
- Gut-associated lymphoid tissue (GALT) dendritic cells (DCs) display a unique ability to generate CCR9+α4β7+ gut-tropic CD8+ effector T cells. We demonstrate efficient induction of CCR9 and α4β7 on CD8+ T cells in mesenteric lymph nodes (MLNs) after oral but not intraperitoneal (i.p.) antigen administration indicating differential targeting of DCs via the oral route. In vitro, lamina propria (LP)–derived DCs were more potent than MLN or Peyer's patch DCs in their ability to generate CCR9+α4β7+ CD8+ T cells. The integrin α chain CD103 (αE) was expressed on almost all LP DCs, a subset of MLN DCs, but on few splenic DCs. CD103+ MLN DCs were reduced in number in CCR7−/− mice and, although CD8+ T cells proliferated in the MLNs of CCR7−/− mice after i.p. but not oral antigen administration, they failed to express CCR9 and had reduced levels of α4β7. Strikingly, although CD103+ and CD103− MLN DCs were equally potent at inducing CD8+ T cell proliferation and IFN-γ production, only CD103+ DCs were capable of generating gut-tropic CD8+ effector T cells in vitro. Collectively, these results demonstrate a unique function for LP-derived CD103+ MLN DCs in the generation of gut-tropic effector T cells.
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