| 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. |
- Sitnicka Quinn, Ewa, et al.
(författare)
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Critical role of FLT3 ligand in IL-7 receptor-independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors
- 2007
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Ingår i: Blood. - Washington, DC : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 110:8, s. 2955-2964
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Tidskriftsartikel (refereegranskat)abstract
- The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow (BM) stem/progenitor cells that continuously replace thymic progenitors remain largely unknown. Herein, we show that fms-like tyrosine kinase 3 (Flt3) ligand (Fl)-deficient mice have distinct reductions in the earliest thymic progenitors in fetal, postnatal, and adult thymus. A critical role of FL in thymopoiesis was particularly evident in the absence of interleukin-7 receptor alpha (IL-7Ralpha) signaling. Fl-/-Il-7r-/- mice have extensive reductions in fetal and postnatal thymic progenitors that result in a loss of active thymopoiesis in adult mice, demonstrating an indispensable role of FL in IL-7Ralpha-independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7Ralpha, in regulation of the earliest lineage-negative (Lin(-)) Lin(-)SCA1+KIT+ (LSK) FLT3(hi) lymphoid-primed multipotent progenitors in BM, demonstrating a key role of FLT3 signaling in regulating the very earliest stages of lymphoid progenitors.
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| 3. |
- 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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| 4. |
- Svensson, Marcus, et al.
(författare)
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Role of CCL25/CCR9 in immune homeostasis and disease
- 2006
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Ingår i: Expert Review of Clinical Immunology. - 1744-666X. ; 2:5, s. 759-773
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Forskningsöversikt (refereegranskat)abstract
- Chemokines constitute a large family of low-molecular-weight proteins (∼10 kDa in size), recognized primarily for their role in directing leukocyte migration under both homeostatic and inflammatory settings. The chemokine CCL25 displays a unique and highly restricted expression pattern compared with other chemokine family members. In the steady state, CCL25 is expressed at high levels primarily in the thymus and small intestine, while its sole functional receptor, CCR9, is expressed on subsets of developing thymocytes and intestinal lymphocytes. Mice that are deficient in CCR9 show relatively normal thymocyte development; however, in competitive transfer experiments, CC99-/- bone-marrow cells are severely disadvantaged in their ability to generate mature T cells compared with wildtype cells. Indeed, expression data and analysis of genetically modified mice suggest that CCL25/CCR9 may be involved in multiple stages of thymocyte development. Recent in vivo studies have demonstrated a role for CCL25/CCR9 in mediating lymphocyte recruitment to the small intestine and in the development of the small intestinal T-cell receptor-γδ T-cell compartment. Finally, CCL25 is expressed in the small intestine of Crohn's disease patients and, in certain inflammatory conditions, outside the small intestine. Together, these results suggest an important role for CCL25/CCR9 in T-cell development and small intestinal immunity and suggest that targeting the CCL25/CCR9 pathway may provide a means to modulate small intestinal immune responses.
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