| 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. |
- Lucas, Beth, et al.
(författare)
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CCRL1/ACKR4 is expressed in key thymic microenvironments but is dispensable for T lymphopoiesis at steady state in adult mice
- 2015
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 45:2, s. 574-583
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Tidskriftsartikel (refereegranskat)abstract
- Thymus colonisation and thymocyte positioning are regulated by interactions between CCR7 and CCR9, and their respective ligands, CCL19/CCL21 and CCL25. The ligands of CCR7 and CCR9 also interact with the atypical receptor CCRL1 (also known as ACKR4), which is expressed in the thymus and has recently been reported to play an important role in normal alpha beta T-cell development. Here, we show that CCRL1 is expressed within the thymic cortex, predominantly by MHC-II(low)CD40(-) cortical thymic epithelial cells and at the subcapsular zone by a population of podoplanin(+) thymic epithelial cells in mice. Interestingly, CCRL1 is also expressed by stromal cells which surround the pericytes of vessels at the corticomedullary junction, the site for progenitor cell entry and mature thymocyte egress from the thymus. We show that CCRL1 suppresses thymocyte progenitor entry into the thymus, however, the thymus size and cellularity are the same in adult WT and CCRL1(-/-) mice. Moreover, CCRL1(-/-) mice have no major perturbations in T-cell populations at different stages of thymic differentiation and development, and have a similar rate of thymocyte migration into the blood. Collectively, our findings argue against a major role for CCRL1 in normal thymus development and function.
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| 3. |
- Sitnik, Katarzyna M, et al.
(författare)
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Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis.
- 2012
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 188:10, s. 4801-4809
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Tidskriftsartikel (refereegranskat)abstract
- The vitamin A metabolite and transcriptional modulator retinoic acid (RA) is recognized as an important regulator of epithelial cell homeostasis in several tissues. Despite the known importance of the epithelial compartment of the thymus in T cell development and selection, the potential role of RA in the regulation of thymic cortical and medullary epithelial cell homeostasis has yet to be addressed. In this study, using fetal thymus organ cultures, we demonstrate that endogenous RA signaling promotes thymic epithelial cell (TEC) cell-cycle exit and restricts TEC cellularity preferentially in the cortical TEC compartment. Combined gene expression, biochemical, and functional analyses identified mesenchymal cells as the major source of RA in the embryonic thymus. In reaggregate culture experiments, thymic mesenchyme was required for RA-dependent regulation of TEC expansion, highlighting the importance of mesenchyme-derived RA in modulating TEC turnover. The RA-generating potential of mesenchymal cells was selectively maintained within a discrete Ly51(int)gp38(+) subset of Ly51(+) mesenchyme in the adult thymus, suggesting a continual role for mesenchymal cell-derived RA in postnatal TEC homeostasis. These findings identify RA signaling as a novel mechanism by which thymic mesenchyme influences TEC development.
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| 4. |
- 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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| 5. |
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| 6. |
- Agace, William, et al.
(författare)
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How vitamin A metabolizing dendritic cells are generated in the gut mucosa.
- 2012
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Ingår i: Trends in Immunology. - : Elsevier BV. - 1471-4981 .- 1471-4906. ; 33, s. 42-48
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Tidskriftsartikel (refereegranskat)abstract
- CD103(+) dendritic cells (DCs) represent the major migratory DC population in the intestinal lamina propria and are believed to play an essential role in the initiation and regulation of mucosal adaptive immune responses. Small intestine (SI) CD103(+) DCs have an enhanced capacity to generate the vitamin A metabolite, retinoic acid, a property that underlies their ability to induce the gut homing receptors CC chemokine receptor 9 and α4β7 on responding T and B cells, and enhance forkhead box P3(+) T regulatory and IgA plasma cell differentiation in vitro. In this review, we discuss the environmental signals that appear to promote vitamin A metabolising activity in SI CD103(+) DCs in the steady state and thus which may contribute to driving the unique nature of SI immune responses.
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| 7. |
- 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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| 8. |
- Agace, William, et al.
(författare)
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T-lymphocyte-epithelial-cell interactions: integrin alpha(E)(CD103)beta(7), LEEP-CAM and chemokines
- 2000
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Ingår i: Current Opinion in Cell Biology. - 0955-0674. ; 12:5, s. 563-568
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Forskningsöversikt (refereegranskat)abstract
- The epithelia are the avascular layers of cells that cover the environment-exposed surfaces of the body. It appears that T cells localize to selected sites in or adjacent to epithelia via the selective expression of adhesion molecules and chemokine receptors on T cells. These bind to counter-receptors and to chemokines expressed by epithelial cells. Recently, there has been an advance in our understanding of the interaction of the alpha(Ebeta7) integrin with its epithelial cell ligand, E-cadherin. In addition, a new adhesion molecule has been identified on non-intestinal epithelial cells, termed lymphocyte-endothelial-epithelial-cell adhesion molecule (LEEP-CAM). Finally, there have been advances in our understanding of the role of skin- or gut-epithelia-derived chemokines in regulating activated T cell homing to these sites.
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| 9. |
- Agace, William, et al.
(författare)
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Thank you to our reviewers!
- 2019
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 12:2, s. 293-295
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Agace, William
(författare)
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The role of the epithelial cell in Escherichia coli induced neutrophil migration into the urinary tract.
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study examined the molecular mechanisms of neutrophil migration to sites of mucosal bacterial infection. (1) Bacterial induction of neutrophil chemotactic cytokines and their role in neutrophil migration. Uropathogenic E.coli were shown to stimulate urinary tract epithelial cells to produce a specific array of cytokines including the neutrophil chemoattractant IL-8. IL-8 production was dependent on the adherence properties of the infecting strain. Deliberate colonisation of the human urinary tract with E.coli induced the local production of IL-8 and levels correlated with urinary neutrophil numbers. The E.coli induced IL-8 supported neutrophil migration across urinary tract epithelial layers in vitro and anti-IL-8 antibody blocked this response. The chemotactically active IL-8 was localised to the epithelial surface and these cells contained IL-8 receptor A and B mRNA. (2) The role of epithelial adhesion molecules in E.coli induced transuroepithelial migration. Uroepithelial cells constitutively expressed ICAM-1 and E.coli augmented ICAM-1 expression. Transuroepithelial neutrophil migration was dependent on epithelial ICAM-1 and neutrophil Mac-1 (CD11b/CD18) expression. Thus urinary tract epithelial cells provide two prerequisites for neutrophil migration to the mucosal lumen; neutrophil chemoattractants and cell adhesion molecules. (3) The role of bacterial fimbriae for the induction of inflammation in the urinary tract. Patients and mice infected with a type 1 positive P fimbriated uropathogenic E.coli clone O1:K1:H7 showed significantly higher inflammatory responses than type 1 negative O1:K1:H7 isolates. Insertion of an npt gene into fimH (encoding the type 1 fimbrial adhesin) of a type 1 positive O1:K1:H7 isolate resulted in the loss of the type 1 fimbrial phenotype and a reduction in virulence.
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