| 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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| 11. |
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| 12. |
- Agace, William W., et al.
(författare)
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Regionalized Development and Maintenance of the Intestinal Adaptive Immune Landscape
- 2017
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613. ; 46:4, s. 532-548
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Forskningsöversikt (refereegranskat)abstract
- The intestinal immune system has the daunting task of protecting us from pathogenic insults while limiting inflammatory responses against the resident commensal microbiota and providing tolerance to food antigens. This role is particularly impressive when one considers the vast mucosal surface and changing landscape that the intestinal immune system must monitor. In this review, we highlight regional differences in the development and composition of the adaptive immune landscape of the intestine and the impact of local intrinsic and environmental factors that shape this process. To conclude, we review the evidence for a critical window of opportunity for early-life exposures that affect immune development and alter disease susceptibility later in life.
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| 13. |
- Ahmadi, Fatemeh, et al.
(författare)
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cDC1-derived IL-27 regulates small intestinal CD4+ T cell homeostasis in mice
- 2023
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 220:3
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Tidskriftsartikel (refereegranskat)abstract
- The small intestinal lamina propria contains large numbers of IFNγ-producing T helper (Th1) cells that play important roles in intestinal homeostasis and host defense, but the mechanisms underlying their development remain poorly understood. Here, we demonstrate that Th1 cells accumulate in the SI-LP after weaning and are maintained there long term. While both Th17 and Th1 cell accumulation in the SI-LP was microbiota dependent, Th1 cell accumulation uniquely required IL-27 and MHCII expression by cDC1. This reflected a requirement for IL-27 signaling in the priming of Th1 cells rather than for their maintenance once in the mucosa. cDC1-derived IL-27 was essential for maintaining the Th1-Th17 balance within the SI-LP, and in its absence, remaining Th1 cells expressed enhanced levels of Th17 signature genes. In conclusion, we identify cDC1-derived IL-27 as a key regulator of SI-LP Th1-Th17 cell homeostasis.
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| 14. |
- 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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| 15. |
- 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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| 16. |
- Arabpour, Mohammad, et al.
(författare)
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ADP-ribosylating adjuvant reveals plasticity in cDC1 cells that drive mucosal Th17 cell development and protection against influenza virus infection
- 2022
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 15:4, s. 745-761
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Tidskriftsartikel (refereegranskat)abstract
- Migratory dendritic cells expressing CD103 are the targets for mucosal vaccines. These belong to either of two lineage-restricted subsets, cDC1 or cDC2 cells, which have been linked to priming of functionally distinct CD4 T cells. However, recent studies have identified plasticity in cDC2 cells with overlapping functions with cDC1 cells, while the converse has not been reported. We genetically engineered a vaccine adjuvant platform that targeted the cholera toxin A1 (CTA1) ADP-ribosylating enzyme to CD103(+) cDC1 and cDC2 cells using a single-chain antibody (scFv) to CD103. Unexpectedly, intranasal immunization with the CTA1-svFcCD103 adjuvant modified cDC1 cells to effectively prime Th17 cells, a function previously limited to cDC2 cells. In fact, cDC2 cells were dispensible, while cDC1 cells, lacking in Batf3-/- mice, were critical. Following intranasal immunizations isolated cDC1 cells from mLN exclusively promoted Rorgt(+) T cells and IL-17, IL-21, and IL-22 production. Strong CD8 T cell responses through antigen cross presentation by cDC1 cells were also observed. Single-cell RNAseq analysis revealed upregulation of Th17-promoting gene signatures in sorted cDC1 cells. Gene expression in isolated cDC2 cells was largely unaffected. Our finding represents a major shift of paradigm as we have documented functional plasticity in cDC1 cells.
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| 17. |
- Bekiaris, Vasileios, et al.
(författare)
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Intestinal dendritic cells in the regulation of mucosal immunity.
- 2014
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Ingår i: Immunological Reviews. - : Wiley. - 1600-065X .- 0105-2896. ; 260:1, s. 86-101
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Forskningsöversikt (refereegranskat)abstract
- The intestine presents a huge surface area to the outside environment, a property that is of critical importance for its key functions in nutrient digestion, absorption, and waste disposal. As such, the intestine is constantly exposed to dietary and microbial-derived foreign antigens, to which immune cells within the mucosa must suitably respond to maintain intestinal integrity, while also providing the ability to mount effective immune responses to potential pathogens. Dendritic cells (DCs) are sentinel immune cells that play a central role in the initiation and differentiation of adaptive immune responses. In the intestinal mucosa, DCs are located diffusely throughout the intestinal lamina propria, within gut-associated lymphoid tissues, including Peyer's patches and smaller lymphoid aggregates, as well as in intestinal-draining lymph nodes, including mesenteric lymph nodes. The recognition that dietary nutrients and microbial communities in the intestine influence both mucosal and systemic immune cell development and function as well as immune-mediated disease has led to an explosion of literature in mucosal immunology in recent years and a growing interest in the functionality of intestinal DCs. In the current review, we discuss recent findings from our group and others that have provided important insights regarding murine and human intestinal lamina propria DCs and highlighted marked developmental and functional heterogeneity within this compartment. A thorough understanding of the role these subsets play in the regulation of intestinal immune homeostasis and inflammation will help to define novel strategies for the treatment of intestinal pathologies and contribute to improved rational design of mucosal vaccines.
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| 18. |
- Benson, Mikael, et al.
(författare)
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Interleukin (IL)-6 and IL-8 in children with febrile urinary tract infection and asymptomatic bacteriuria
- 1996
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 174:5, s. 1080-1084
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Tidskriftsartikel (refereegranskat)abstract
- Urine and serum interleukin (IL)-6 and IL-8 responses were higher in children with febrile urinary tract infection (n = 61) than in those with asymptomatic bacteriuria (n = 39). By univariate analysis, cytokine levels were related to age, sex, reflux, renal scarring, urine leukocytes, C- reactive protein (CRP), erythrocyte sedimentation rate (ESR), and bacterial properties (P fimbriae but not hemolysin). Multivariate modeling showed that urine IL-6 responds were higher in girls than boys, increased with age, and were positively associated with CRP, ESR, serum IL-6, and urine leukocyte counts. The urine IL-8 response was not influenced by age, but it was influenced by P fimbriae and was associated with ESR, CRP, urine leukocytes, and female sex. The results show that cytokine responses to urinary tract infection vary with the severity of infection and that cytokine activation is influenced by a variety of host and bacterial variables.
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| 19. |
- Burger, Nicole B., et al.
(författare)
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Involvement of neurons and retinoic acid in lymphatic development: new insights in increased nuchal translucency
- 2014
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Ingår i: Prenatal Diagnosis. - : Wiley. - 1097-0223 .- 0197-3851. ; 34:13, s. 1312-1319
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveIncreased nuchal translucency originates from disturbed lymphatic development. Abnormal neural crest cell (NCC) migration may be involved in lymphatic development. Because both neuronal and lymphatic development share retinoic acid (RA) as a common factor, this study investigated the involvement of NCCs and RA in specific steps in lymphatic endothelial cell (LEC) differentiation and nuchal edema, which is the morphological equivalent of increased nuchal translucency. MethodsMouse embryos in which all NCCs were fluorescently labeled (Wnt1-Cre;Rosa26(eYfp)), reporter embryos for in vivo RA activity (DR5-luciferase) and embryos with absent (Raldh2(-/-)) or in utero inhibition of RA signaling (BMS493) were investigated. Immunofluorescence using markers for blood vessels, lymphatic endothelium and neurons was applied. Flow cytometry was performed to measure specific LEC populations. ResultsCranial nerves were consistently close to the jugular lymph sac (JLS), in which NCCs were identified. In the absence of RA synthesis, enlarged JLS and nuchal edema were observed. Inhibiting RA signaling in utero resulted in a significantly higher amount of precursor-LECs at the expense of mature LECs and caused nuchal edema. ConclusionsNeural crest cells are involved in lymphatic development. RA is required for differentiation into mature LECs. Blocking RA signaling in mouse embryos results in abnormal lymphatic development and nuchal edema. (c) 2014 John Wiley & Sons, Ltd.
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| 20. |
- Cerovic, V, et al.
(författare)
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Lymph-borne CD8α(+) dendritic cells are uniquely able to cross-prime CD8(+) T cells with antigen acquired from intestinal epithelial cells.
- 2015
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Ingår i: Mucosal immunology. - : Elsevier BV. - 1935-3456 .- 1933-0219. ; 8, s. 38-48
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Tidskriftsartikel (refereegranskat)abstract
- Cross-presentation of cellular antigens is crucial for priming CD8(+) T cells, and generating immunity to intracellular pathogens-particularly viruses. It is unclear which intestinal phagocytes perform this function in vivo. To address this, we examined dendritic cells (DCs) from the intestinal lymph of IFABP-tOVA 232-4 mice, which express ovalbumin in small intestinal epithelial cells (IECs). Among lymph DCs (LDCs) only CD103(+) CD11b(-) CD8α(+) DCs cross-present IEC-derived ovalbumin to CD8(+) OT-I T cells. Similarly, in the mesenteric lymph nodes (MLNs), cross-presentation of IEC-ovalbumin was limited to the CD11c(+) MHCII(hi) CD8α(+) migratory DCs, but absent from all other subsets, including the resident CD8α(hi) DCs. Crucially, delivery of purified CD8α(+) LDCs, but not other LDC subsets, into the MLN subcapsular lymphatic sinus induced proliferation of ovalbumin-specific, gut-tropic CD8(+) T cells in vivo. Finally, in 232-4 mice treated with R848, CD8α(+) LDCs were uniquely able to cross-prime interferon γ-producing CD8(+) T cells and drive their migration to the intestine. Our results clearly demonstrate that migrating CD8α(+) intestinal DCs are indispensable for cross-presentation of cellular antigens and, in conditions of inflammation, for the initial differentiation of effector CD8(+) T cells. They may therefore represent an important target for the development of antiviral vaccinations.Mucosal Immunology advance online publication, 21 May 2014; doi:10.1038/mi.2014.40.
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| 21. |
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| 22. |
- Cossarizza, A., et al.
(författare)
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Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
- 2019
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 49:10, s. 1457-1973
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Tidskriftsartikel (refereegranskat)abstract
- These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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| 23. |
- Eguíluz-Gracia, Ibon, et al.
(författare)
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Long-Term persistence of human donor alveolar macrophages in lung transplant recipients
- 2016
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 71:11, s. 1006-1011
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Tidskriftsartikel (refereegranskat)abstract
- Background Alveolar macrophages (AMFs) are critical regulators of lung function, and may participate in graft rejection following lung transplantation. Recent studies in experimental animals suggest that most AMFs are self-maintaining cells of embryonic origin, but knowledge about the ontogeny and life span of human AMFs is scarce. Methods To follow the origin and longevity of AMFs in patients with lung transplantation for more than 100â €..weeks, we obtained transbronchial biopsies from 10 gender-mismatched patients with lung transplantation. These were subjected to combined in situ hybridisation for X/Y chromosomes and immunofluorescence staining for macrophage markers. Moreover, development of AMFs in humanised mice reconstituted with CD34+ umbilical cord-derived cells was assessed. Results The number of donor-derived AMFs was unchanged during the 2â €..year post-Transplantation period. A fraction of the AMFs proliferated locally, demonstrating that at least a subset of human AMFs have the capacity to self-renew. Lungs of humanised mice were found to abundantly contain populations of human AMFs expressing markers compatible with a monocyte origin. Moreover, in patients with lung transplantation we found that recipient monocytes seeded the alveoli early after transplantation, and showed subsequent phenotypical changes consistent with differentiation into proliferating mature AMFs. This resulted in a stable mixed chimerism between donor and recipient AMFs throughout the 2-year period. Conclusions The finding that human AMFs are maintained in the lung parenchyma for several years indicates that pulmonary macrophage transplantation can be a feasible therapeutic option for patients with diseases caused by dysfunctional AMFs. Moreover, in a lung transplantation setting, long-Term persistence of donor AMFs may be important for the development of chronic graft rejection.
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| 24. |
- Ericsson, Anna, et al.
(författare)
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CCL25/CCR9 promotes the induction and function of CD103 on intestinal intraepithelial lymphocytes.
- 2004
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 34:10, s. 2720-2729
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Tidskriftsartikel (refereegranskat)abstract
- The integrin CD103 and the chemokine receptor CCR9 are co-expressed on small intestinal CD8+ intraepithelial lymphocytes (IEL), naïve murine CD8+ T cells and by a small population of effector/memory CD8+ T cells, indicating a potential role for CCR9 in regulating CD103 expression and function. Here, we demonstrate that CD103, in contrast to CCR9, is down-regulated on CD8+ T cells following their activation in mesenteric lymph nodes and that effector CD8+ T cells upon initial entry into the small intestinal epithelium are CCR9+CD103-. CD103 was rapidly induced on wild-type CD8+ T cells subsequent to their entry into the small intestinal epithelium, however, CCR9-/- CD8+ T cells exhibited a significant delay in CD103 induction at this site. In addition, the CCR9 ligand, CCL25, that is constitutively expressed in the small intestinal epithelium, induced transient, dose-dependent and pertussis toxin-sensitive CD103-mediated adhesion of CD8+ small intestinal IEL to a murine E-cadherin human Fc (mEFc) fusion protein. Together, these results demonstrate a role for CCR9/CCL25 in promoting the induction and function of CD103 on CD8+ IEL and suggest that this chemokine receptor/chemokine pair may function to regulate lymphocyte-epithelial interactions in the small intestinal mucosa.
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| 25. |
- Ericsson, Anna, et al.
(författare)
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CCL25 Enhances CD103-Mediated Lymphocyte Adhesion to E-Cadherin.
- 2004
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1029, s. 334-336
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Tidskriftsartikel (refereegranskat)abstract
- Our results demonstrate that (1) CD103 is upregulated on CD8(+) T cells subsequent to their entry into the small intestinal epithelium, and (2) that the chemokine CCL25 enhances CD103-mediated adhesion to E-cadherin. These results suggest a novel role for chemokines in modulating interactions between lymphocytes and epithelial cells at mucosal surfaces.
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| 26. |
- 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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| 27. |
- Fenton, Thomas M., et al.
(författare)
-
Immune Profiling of Human Gut-Associated Lymphoid Tissue Identifies a Role for Isolated Lymphoid Follicles in Priming of Region-Specific Immunity
- 2020
-
Ingår i: Immunity. - : Elsevier BV. - 1074-7613. ; 52:3, s. 557-570
-
Tidskriftsartikel (refereegranskat)abstract
- The intestine contains some of the most diverse and complex immune compartments in the body. Here we describe a method for isolating human gut-associated lymphoid tissues (GALTs) that allows unprecedented profiling of the adaptive immune system in submucosal and mucosal isolated lymphoid follicles (SM-ILFs and M-ILFs, respectively) as well as in GALT-free intestinal lamina propria (LP). SM-ILF and M-ILF showed distinct patterns of distribution along the length of the intestine, were linked to the systemic circulation through MAdCAM-1+ high endothelial venules and efferent lymphatics, and had immune profiles consistent with immune-inductive sites. IgA sequencing analysis indicated that human ILFs are sites where intestinal adaptive immune responses are initiated in an anatomically restricted manner. Our findings position ILFs as key inductive hubs for regional immunity in the human intestine, and the methods presented will allow future assessment of these compartments in health and disease.
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| 28. |
- Fernández-Santoscoy, Maria, et al.
(författare)
-
A reduced population of CD103(+)CD11b(+) dendritic cells has a limited impact on oral Salmonella infection
- 2016
-
Ingår i: Immunology Letters. - : Elsevier BV. - 0165-2478. ; 176, s. 72-80
-
Tidskriftsartikel (refereegranskat)abstract
- CD103(+)CD11b(+) dendritic cells (DC) are the major migratory DC subset in the small intestine lamina propria (siLP) and their survival is dependent on the transcription factor interferon regulatory factor 4 (IRF4). Mice with a DC-specific deletion of irf4 (CD11c-cre.Irf4 mice) have reduced mucosal CD103(+)CD11b(+) DC and altered T cell differentiation to protein antigen. The influence of CD103(+)CD11b(+) DC on oral infection with the gastrointestinal pathogen Salmonella, however, is poorly understood and is investigated here. We show that, despite being infected with Salmonella, CD11c-cre.lrf4 mice (called Cre(+) mice) conserve the reduction in CD103(+)CD11b(+) DC observed in naive Cre(+) mice, particularly in the mesenteric lymph nodes (MLN) but also in the siLP at day 3 post infection. Moreover, Salmonella-infected Cre(+) mice have a similar bacterial burden in intestinal tissues (siLP, MLN and Peyer's patches) as well as the spleen compared to infected Cre-controls. The T cell compartment, including the frequency of IFN-gamma and IL-17-producing T cells, is not altered in intestinal tissues of Salmonella-infected Cre(+) mice relative to infected Cre-controls. In addition, no difference between infected Cre(+) and Cre-mice was observed in either the concentration of IL-6 or IL-17 in whole tissue lysates of siLP, MLN or Peyer's patches or in the serum concentration of Salmonella-specific IgG and IgM. Overall the data suggest that the reduction of CD103(+)CD11b(+) DC in Cre(+) mice has little if any impact on Salmonella burden in infected tissues or eliciting effector functions important in host survival at later stages of the infection. (C) 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.
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| 29. |
- Flores-Langarica, Adriana, et al.
(författare)
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Intestinal CD103+CD11b+ cDC2 conventional dendritic cells are required for primary CD4+ T and B cell responses to soluble flagellin
- 2018
-
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9:OCT
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic immunization with soluble flagellin (sFliC) from Salmonella Typhimurium induces mucosal responses, offering potential as an adjuvant platform for vaccines. Moreover, this engagement of mucosal immunity is necessary for optimal systemic immunity, demonstrating an interaction between these two semi-autonomous immune systems. Although TLR5 and CD103+CD11b+ cDC2 contribute to this process, the relationship between these is unclear in the early activation of CD4+ T cells and the development of antigen-specific B cell responses. In this work, we use TLR5-deficient mice and CD11c-cre.Irf4fl/fl mice (which have reduced numbers of cDC2, particularly intestinal CD103+CD11b+ cDCs), to address these points by studying the responses concurrently in the spleen and the mesenteric lymph nodes (MLN). We show that CD103+CD11b+ cDC2 respond rapidly and accumulate in the MLN after immunization with sFliC in a TLR5-dependent manner. Furthermore, we identify that whilst CD103+CD11b+ cDC2 are essential for the induction of primary T and B cell responses in the mucosa, they do not play such a central role for the induction of these responses in the spleen. Additionally, we show the involvement of CD103+CD11b+ cDC2 in the induction of Th2-associated responses. CD11c-cre.Irf4fl/fl mice showed a reduced primary FliC-specific Th2-associated IgG1 responses, but enhanced Th1-associated IgG2c responses. These data expand our current understanding of the mucosal immune responses promoted by sFliC and highlights the potential of this adjuvant for vaccine usage by taking advantage of the functionality of mucosal CD103+CD11b+ cDC2.
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| 30. |
- Godaly, Gabriela, et al.
(författare)
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Role of epithelial interleukin-8 (IL-8) and neutrophil IL-8 receptor A in Escherichia coli-induced transuroepithelial neutrophil migration
- 1997
-
Ingår i: Infection and Immunity. - 1098-5522. ; 65:8, s. 3451-3456
-
Tidskriftsartikel (refereegranskat)abstract
- Escherichia coli stimulates neutrophil migration across human uroepithelial cell layers. This study investigated the role of the neutrophil chemokine interleukin-8 (IL-8) in this process. E. coli and IL-1alpha stimulated urinary tract epithelial layers to secrete IL-8 and induced transepithelial neutrophil migration. Anti-IL-8 antibody reduced neutrophil migration across epithelial cell layers, indicating a central role for this chemokine in the migration process. Furthermore, addition of recombinant IL-8 to unstimulated cell layers was sufficient to induce migration. The IL-8 dependence of neutrophil migration was maintained after removal of soluble IL-8 by washing of the cell layers. Flow cytometry analysis with fluorescein isothiocyanate-labelled IL-8 confirmed IL-8's ability to bind to the epithelial cell surface. Indirect immunofluorescence with confocal laser scanning microscopy showed that IL-8 associated with the epithelial cell layers. Prior incubation of neutrophils with antibodies to IL-8 receptor A (IL-8RA) reduced neutrophil migration. Anti-IL-8 RB antibody had no effect on neutrophil migration. These results demonstrate that IL-8 plays a key role in E. coli- or IL-1alpha-induced transuroepithelial migration and suggest that epithelial cell-produced IL-8 interacts with IL-8RA on the neutrophil surface.
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| 31. |
- Hang, Long, et al.
(författare)
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Macrophage inflammatory protein-2 is required for neutrophil passage across the epithelial barrier of the infected urinary tract
- 1999
-
Ingår i: Journal of Immunology. - 1550-6606. ; 162:5, s. 3037-3044
-
Tidskriftsartikel (refereegranskat)abstract
- IL-8 is a major human neutrophil chemoattractant at mucosal infection sites. This study examined the C-X-C chemokine response to mucosal infection, and, specifically, the role of macrophage inflammatory protein (MIP)-2, one of the mouse IL-8 equivalents, for neutrophil-epithelial interactions. Following intravesical Escherichia coli infection, several C-X-C chemokines were secreted into the urine, but only MIP-2 concentrations correlated to neutrophil numbers. Tissue quantitation demonstrated that kidney MIP-2 production was triggered by infection, and immunohistochemistry identified the kidney epithelium as a main source of MIP-2. Treatment with anti-MIP-2 Ab reduced the urine neutrophil numbers, but the mice had normal tissue neutrophil levels. By immunohistochemistry, the neutrophils were found in aggregates under the pelvic epithelium, but in control mice the neutrophils crossed the urothelium into the urine. The results demonstrate that different chemokines direct neutrophil migration from the bloodstream to the lamina propria and across the epithelium and that MIP-2 serves the latter function. These findings suggest that neutrophils cross epithelial cell barriers in a highly regulated manner in response to chemokines elaborated at this site. This is yet another mechanism that defines the mucosal compartment and differentiates the local from the systemic host response.
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| 32. |
- Hedges, Spencer R., et al.
(författare)
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Epithelial cytokine responses and mucosal cytokine networks
- 1995
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Ingår i: Trends in Microbiology. - 0966-842X. ; 3:7, s. 266-270
-
Forskningsöversikt (refereegranskat)abstract
- Localized at the border between the external environment and the internal tissue, epithelial cells are exposed to stimulants from two directions. Microorganisms in the lumen can activate the transcription of cytokine mRNA and cytokine secretion, and cytokines in the mucosal environment can modify endogenous and microbially induced epithelial cytokine responses. Epithelial cells thus actively participate in mucosal immunity and inflammation.
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| 33. |
- Hedges, Spencer R., et al.
(författare)
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Immunoregulatory cytokines modify Escherichia coli induced uroepithelial cell IL-6 and IL-8 responses
- 1996
-
Ingår i: Cytokine. - : Elsevier BV. - 1043-4666. ; 8:9, s. 686-697
-
Tidskriftsartikel (refereegranskat)abstract
- This study analysed the effects of immunoregulatory cytokines on uroepithelial cell cytokine responses. The A-498 human kidney cell line was treated with the interleukins IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, interferon gamma (IFN-α) and transforming growth factor beta (TGF-β1). Secreted IL-6 and IL-8 were quantitated by enzyme-linked immunoabsorbent assay (ELISA) and bioassay; IL-6 and IL-8 mRNA species were quantitated by reverse transcriptase polymerase chain reaction (RT-PCR). IL-4, IL-13, IFN-γ, and TGF-β1, but not IL-2, IL-5, IL-10 or IL-12, stimulated IL-6 secretion. At high concentrations, IL-4 and IL-13 stimulated low levels of IL-8 secretion. Immunoregulatory cytokines were analysed for their ability to modify the A-498 cells' IL-6 and IL-8 secretion in response to Escherichia coli. IL-5, IL-12, IL-13 and TGF-β1 additively enhanced the bacterially induced IL-6 secretion, but they did not affect IL-8 secretion. The strongest affects on uroepithelial cell IL-6 and IL-8 responses in the presence of bacteria were observed in conjunction with IL-4 and IFN-α. IL-4 induced IL-6 production in synergy with E. coli. IFN-α both enhanced and inhibited IL-6 and IL-8 responses in combination with E. coli, depending on the order of stimulant addition. The results demonstrate that immunoregulatory cytokines can modify the uroepithelial cell responses to bacteria in vitro. In this way T cells may regulate the cytokine responses of uroepithelial and possibly other mucosal epithelial cells in vivo.
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| 34. |
- Holmkvist, Petra, et al.
(författare)
-
A major population of mucosal memory CD4(+) T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality.
- 2015
-
Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 8:3, s. 545-558
-
Tidskriftsartikel (refereegranskat)abstract
- Mucosal tissues contain large numbers of memory CD4(+) T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4(+) T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα(+)DR3(+)CD4(+) T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα(+)DR3(+)CD4(+) T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα(+)DR3(+) CD4(+) T cells may contribute to antigen-independent innate responses at barrier surfaces.Mucosal Immunology advance online publication, 1 October 2014; doi:10.1038/mi.2014.87.
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| 35. |
- Holmkvist, Petra, et al.
(författare)
-
IL-18Rα-deficient CD4+ T cells induce intestinal inflammation in the CD45RBhi transfer model of colitis despite impaired innate responsiveness
- 2016
-
Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980. ; 46:6, s. 1371-1382
-
Tidskriftsartikel (refereegranskat)abstract
- IL-18 has been implicated in inflammatory bowel disease (IBD), however its role in the regulation of intestinal CD4+ T-cell function remains unclear. Here we show that murine intestinal CD4+ T cells express high levels of IL-18Rα and provide evidence that IL-18Rα expression is induced on these cells subsequent to their entry into the intestinal mucosa. Using the CD45RBhi T-cell transfer colitis model, we show that IL-18Rα is expressed on IFN-γ+, IL-17+, and IL-17+IFN-γ+ effector CD4+ T cells in the inflamed colonic lamina propria (cLP) and mesenteric lymph node (MLN) and is required for the optimal generation and/or maintenance of IFN-γ-producing cells in the cLP. In the steady state and during colitis, TCR-independent cytokine-induced IFN-γ and IL-17 production by intestinal CD4+ T cells was largely IL-18Rα−dependent. Despite these findings however, IL-18Rα−deficient CD4+ T cells induced comparable intestinal pathology to WT CD4+ T cells. These findings suggest that IL-18-dependent cytokine induced activation of CD4+ T cells is not critical for the development of T-cell-mediated colitis.
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| 36. |
- Hägerbrand, Karin, et al.
(författare)
-
MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103(+) Dendritic Cells Independently of TNF-alpha and the Gut Microbiota
- 2015
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 195:6, s. 2888-2899
-
Tidskriftsartikel (refereegranskat)abstract
- Intestinal homeostasis and induction of systemic tolerance to fed Ags (i.e., oral tolerance) rely on the steady-state migration of small intestinal lamina propria dendritic cells (DCs) into draining mesenteric lymph nodes (MLN). The majority of these migratory DCs express the a integrin chain CD103, and in this study we demonstrate that the steady-state mobilization of CD103(+) DCs into the MLN is in part governed by the IL-1R family/TLR signaling adaptor molecule MyD88. Similar to mice with complete MyD88 deficiency, specific deletion of MyD88 in DCs resulted in a 50-60% reduction in short-term accumulation of both CD103(+)CD11b(+) and CD103(+)CD11b(-) DCs in the MLN. DC migration was independent of caspase-1, which is responsible for the inflammasome-dependent proteolytic activation of IL-1 cytokine family members, and was not affected by treatment with broad-spectrum antibiotics. Consistent with the latter finding, the proportion and phenotypic composition of DCs were similar in mesenteric lymph from germ-free and conventionally housed mice. Although TNF-alpha was required for CD103(+) DC migration to the MLN after oral administration of the TLR7 agonist R848, it was not required for the steady-state migration of these cells. Similarly, TLR signaling through the adaptor molecule Toll/IL-1R domain-containing adapter inducing IFN-beta and downstream production of type I IFN were not required for steady-state CD103(+) DC migration. Taken together, our results demonstrate that MyD88 signaling in DCs, independently of the microbiota and TNF-alpha, is required for optimal steady-state migration of small intestinal lamina propria CD103(+) DCs into the MLN.
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| 37. |
- Isaksson, Magnus, 1975-
(författare)
-
Initiation of Autoimmunity in Experimental Autoimmune Encephalomyelitis
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The events that trigger an autoimmune disease remain largely unknown. To study these events animal models are necessary because symptoms of autoimmune diseases are preceded by a long asymptomatic period in humans.Experimental autoimmune encephalomyelitis (EAE) is the best characterized model for cell mediated autoimmunity and an animal model for the human disease multiple sclerosis. EAE is induced in rodents by immunization with myelin antigens (Ags) together with adjuvants. After immunization, T cells are primed in the periphery by Ag presenting cells and subsequently invade the central nervous system where they mediate parenchymal inflammation, resulting in demyelination and clinical symptoms of an ascending paralysis. It is now generally recognised that the main cell type mediating EAE is the T helper type 17 (Th17) cell.Tolerance to EAE can be attained by DNA vaccination, but how the immune response against the myelin Ags is abrogated after DNA vaccination is not known. By employing short interfering RNA technology, induction of the innate immune signalling molecule interferon (IFN) -β was found to be necessary for the protective effect of DNA vaccination in EAE. In addition, DNA vaccination inhibited subsequent autoimmune Th17 cell responses.The Toll-like receptors (TLRs) of the innate immune system have evolved to recognise conserved molecular structures on microbes and signalling through them almost exclusively converge on the molecule MyD88. Signalling via MyD88 was found to be required for induction of EAE since mice deficient in this molecule did not develop disease. Upstream signalling via TLR4 and TLR9 had tolerogenic properties.In studies of Ag presentation in EAE, two major subtypes of dendritic cells (DCs) were examined. Plasmacytoid DCs were found to have a promoting role in the induction of EAE, partly via type 1 IFNs. Myeloid DCs had a redundant role in the induction phase of EAE, neither disease severity nor encephalitogenic Th17 responses were affected by their absence during priming.These studies further demonstrate that the cells and molecules of the innate immune system exhibit a crucial role in controlling the adaptive immune system which mediates tissue damage in autoimmune diseases.
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| 38. |
- Jaensson Gyllenbäck, Elin, et al.
(författare)
-
Bile retinoids imprint intestinal CD103(+) dendritic cells with the ability to generate gut-tropic T cells.
- 2011
-
Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 4, s. 438-447
-
Tidskriftsartikel (refereegranskat)abstract
- Small intestinal lamina propria (SI-LP) CD103(+) dendritic cells (DCs) are imprinted with an ability to metabolize vitamin A (retinol), a property underlying their enhanced capacity to induce the gut-homing receptors CC chemokine receptor-9 and α4β7 on responding T cells. In this study, we demonstrate that imprinting of CD103(+) DCs is itself critically dependent on vitamin A and occurs locally within the small intestine (SI). The major vitamin A metabolite retinoic acid (RA) induced retinol-metabolizing activity in DCs both in vitro and in vivo, suggesting a direct role for RA in this process. Consistent with this, SI-LP CD103(+) DCs constitutively received RA signals in vivo at significantly higher levels than did colonic CD103(+) DCs. Remarkably, SI CD103(+) DCs remained imprinted in mice depleted of dietary but not of systemic retinol. We found that bile contained high levels of retinol, induced RA receptor-dependent retinol-metabolizing activity in bone marrow-derived DCs, and imprinted these cells with the ability to generate gut-tropic T cells. Taken together, these results suggest a novel and unexpected role for bile in SI-LP CD103(+) DC imprinting.Mucosal Immunology advance online publication 2 February 2011. doi:10.1038/mi.2010.91.
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| 39. |
- Jaensson Gyllenbäck, Elin, et al.
(författare)
-
Small intestinal CD103(+) dendritic cells display unique functional properties that are conserved between mice and humans
- 2008
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205:9, s. 2139-2149
-
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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| 40. |
- Jensen, Benjamin A H, et al.
(författare)
-
Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism
- 2021
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Interactions between host and gut microbial communities are modulated by diets and play pivotal roles in immunological homeostasis and health. We show that exchanging the protein source in a high fat, high sugar, westernized diet from casein to whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath is sufficient to reverse western diet-induced changes in the gut microbiota to a state resembling that of lean, low fat diet-fed mice, both under mild thermal stress (T22 °C) and at thermoneutrality (T30 °C). Concomitant with microbiota changes, mice fed the Methylococcus-based western diet exhibit improved glucose regulation, reduced body and liver fat, and diminished hepatic immune infiltration. Intake of the Methylococcu-based diet markedly boosts Parabacteroides abundances in a manner depending on adaptive immunity, and upregulates triple positive (Foxp3+RORγt+IL-17+) regulatory T cells in the small and large intestine. Collectively, these data point to the potential for leveraging the use of McB lysates to improve immunometabolic homeostasis.
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| 41. |
- Joeris, Thorsten, et al.
(författare)
-
Intestinal cDC1 drive cross-tolerance to epithelial-derived antigen via induction of FoxP3+CD8+ Tregs
- 2021
-
Ingår i: Science Immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 6:60
-
Tidskriftsartikel (refereegranskat)abstract
- Although CD8+ T cell tolerance to tissue-specific antigen (TSA) is essential for host homeostasis, the mechanisms underlying peripheral cross-tolerance and whether they may differ between tissue sites remain to be fully elucidated. Here, we demonstrate that peripheral cross-tolerance to intestinal epithelial cell (IEC)–derived antigen involves the generation and suppressive function of FoxP3+CD8+ T cells. FoxP3+CD8+ Treg generation was dependent on intestinal cDC1, whose absence led to a break of tolerance and epithelial destruction. Mechanistically, intestinal cDC1-derived PD-L1, TGFβ, and retinoic acid contributed to the generation of gut-tropic CCR9+CD103+FoxP3+CD8+ Tregs. Last, CD103-deficient CD8+ T cells lacked tolerogenic activity in vivo, indicating a role for CD103 in FoxP3+CD8+ Treg function. Our results describe a role for FoxP3+CD8+ Tregs in cross-tolerance in the intestine for which development requires intestinal cDC1.
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| 42. |
- Johansson, C, et al.
(författare)
-
Differential expression of chemokine receptors on human IgA+ and IgG+ B cells.
- 2005
-
Ingår i: Clinical and experimental immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 141:2, s. 279-87
-
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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| 43. |
- Johansson Lindbom, Bengt, et al.
(författare)
-
Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing.
- 2005
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 202:8, s. 1063-1073
-
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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| 44. |
- Johansson Lindbom, Bengt, et al.
(författare)
-
Generation of gut-homing T cells and their localization to the small intestinal mucosa.
- 2007
-
Ingår i: Immunological Reviews. - 1600-065X. ; 215:1, s. 226-242
-
Forskningsöversikt (refereegranskat)abstract
- The intestinal mucosa represents the largest body surface toward the external environment and harbors numerous T lymphocytes that take up resident within the intestinal epithelium or in the underlying lamina propria (LP). The intraepithelial lymphocytes include subsets of 'unconventional' T cells with unclear ontogeny and reactivity that localize to this site independently of antigen-specific activation in secondary lymphoid organs. In contrast, the majority of the 'conventional' gut T cells are recruited into the intestinal mucosa subsequent to their activation in intestinal inductive sites, including Peyer's patches (PPs) and mesenteric lymph nodes (MLNs). T cells homing to the small intestine express a distinct pattern of homing molecules, allowing them to interact with and transmigrate across intestinal postcapillary endothelium. At least some of these homing molecules, including the integrin alpha(4)beta(7) and the chemokine receptor CCR9, are induced on T cells during their activation in PPs or MLNs. Mucosal dendritic cells (DCs) play a key role in this process, but not all intestinal DCs possess the ability to confer a gut-homing capacity to T cells. Instead, functionally specialized CD103(+) DCs derived from the small intestinal LP appear to selectively regulate T-cell homing to the small intestine.
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| 45. |
- Johansson Lindbom, Bengt, et al.
(författare)
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Selective Generation of Gut Tropic T Cells in Gut-associated Lymphoid Tissue (GALT): Requirement for GALT Dendritic Cells and Adjuvant.
- 2003
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 198:6, s. 963-969
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Tidskriftsartikel (refereegranskat)abstract
- n the current study, we address the underlying mechanism for the selective generation of gut-homing T cells in the gut-associated lymphoid tissues (GALT). We demonstrate that DCs in the GALT are unique in their capacity to establish T cell gut tropism but in vivo only confer this property to T cells in the presence of DC maturational stimuli, including toll-like receptor-dependent and -independent adjuvants. Thus, DCs from mesenteric LNs (MLNs), but not from spleen, supported expression of the chemokine receptor CCR9 and integrin {alpha}4ß7 by activated CD8+ T cells. While DCs were also required for an efficient down-regulation of CD62L, this function was not restricted to MLN DCs. In an adoptive CD8+ T cell transfer model, antigen-specific T cells entering the small intestinal epithelium were homogeneously CCR9+{alpha}4ß7+CD62Llow, and this phenotype was only generated in GALT and in the presence of adjuvant. Consistent with the CCR9+ phenotype of the gut-homing T cells, CCR9 was found to play a critical role in the localization of T cells to the small intestinal epithelium. Together, these results demonstrate that GALT DCs and T cell expression of CCR9 play critical and integrated roles during T cell homing to the gut.
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| 46. |
- Johansson Lindbom, Bengt, et al.
(författare)
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Vitamin A helps gut T cells find their way in the dark.
- 2004
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 10:12, s. 1300-1301
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Tidskriftsartikel (refereegranskat)abstract
- Once activated, some T cells home to distinct sites in the body, such as the intestine and inflamed skin. Research in mice shows that dendritic cells in the gut produce a derivative of vitamin A, retinoic acid, that gives T cells directions.
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| 47. |
- Jørgensen, Peter B., et al.
(författare)
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Identification, isolation and analysis of human gut-associated lymphoid tissues
- 2021
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Ingår i: Nature Protocols. - : Springer Science and Business Media LLC. - 1754-2189 .- 1750-2799. ; 16:4, s. 2051-2067
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Tidskriftsartikel (refereegranskat)abstract
- Gut-associated lymphoid tissues (GALTs) comprise key intestinal immune inductive sites, including the Peyer’s patches of the small intestine and different types of isolated lymphoid follicle (ILF) found along the length of the gut. Our understanding of human GALT is limited due to a lack of protocols for their isolation. Here we describe a technique that, uniquely among intestinal cell isolation protocols, allows identification and isolation of all human GALT, as well as GALT-free intestinal lamina propria (LP). The technique involves the mechanical separation of intestinal mucosa from the submucosa, allowing the identification and isolation of submucosal ILF (SM-ILF), LP-embedded mucosal ILF (M-ILF) and LP free of contaminating lymphoid tissue. Individual SM-ILF, M-ILF and Peyer’s patch follicles can be subsequently digested for downstream cellular and molecular characterization. The technique, which takes 4–10 h, will be useful for researchers interested in intestinal immune development and function in health and disease.
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| 48. |
- Jørgensen, Peter B, et al.
(författare)
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The porcine large intestine contains developmentally distinct submucosal lymphoid clusters and mucosal isolated lymphoid follicles
- 2022
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Ingår i: Developmental and Comparative Immunology. - : Elsevier BV. - 0145-305X. ; 131
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Tidskriftsartikel (refereegranskat)abstract
- Gut-associated lymphoid tissues (GALT) serve as key priming sites for intestinal adaptive immune responses. Most of our understanding of GALT function and development arises from studies in mice. However, the diversity, structure and cellular composition of GALT differs markedly between mammalian species and the developmental window in which distinct GALT structures develop in large mammals remains poorly understood. Given the importance of pigs as models of human disease, as well as their role in livestock production, we adapted a recently developed protocol for the isolation of human GALT to assess the diversity, development and immune composition of large intestinal GALT in neonatal and adult pigs. We demonstrate that the large intestine of adult pigs contains two major GALT types; multifollicular submucosal GALT that we term submucosal lymphoid clusters (SLC) which develop prenatally, and as yet undescribed mucosal isolated lymphoid follicles (M-ILF), which arise after birth. Using confocal laser microscopy and flow cytometry, we additionally assess the microanatomy and lymphocyte composition of SLC and M-ILF, compare them to jejunal Peyer's patches (PP), and describe the maturation of these structures. Collectively, our results provide a deeper understanding of the diversity and development of GALT within the porcine large intestine.
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| 49. |
- Kotarsky, Knut, et al.
(författare)
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A novel role for constitutively expressed epithelial-derived chemokines as antibacterial peptides in the intestinal mucosa.
- 2010
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 3, s. 40-48
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal-derived chemokines have a central role in orchestrating immune cell influx into the normal and inflamed intestine. Here, we identify the chemokine CCL6 as one of the most abundant chemokines constitutively expressed by both murine small intestinal and colonic epithelial cells. CCL6 protein localized to crypt epithelial cells, was detected in the gut lumen and reached high concentrations at the mucosal surface. Its expression was further enhanced in the small intestine following in vivo administration of LPS or after stimulation of the small intestinal epithelial cell line, mIC(c12), with IFNgamma, IL-4 or TNFalpha. Recombinant- and intestinal-derived CCL6 bound to a subset of the intestinal microflora and displayed antibacterial activity. Finally, the human homologs to CCL6, CCL14 and CCL15 were also constitutively expressed at high levels in human intestinal epithelium, were further enhanced in inflammatory bowel disease and displayed similar antibacterial activity. These findings identify a novel role for constitutively expressed, epithelial-derived chemokines as antimicrobial peptides in the intestinal mucosa.Mucosal Immunology advance online publication 7 October 2009. doi:10.1038/mi.2009.115.
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| 50. |
- Kunkel, E J, et al.
(författare)
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Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity
- 2000
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Ingår i: Journal of Experimental Medicine. - 1540-9538. ; 192:5, s. 761-768
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Tidskriftsartikel (refereegranskat)abstract
- The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4(+) and CD8(+) T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9(+), and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9(-). TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.
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