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Title: The role of TNF-α converting enzyme (TACE:ADAM17) in L-selection shedding and lymphocyte migration
Author: Yates, Emma-Kate
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2005
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The leucocyte adhesion molecule L-selectin mediates the tethering and rolling of lymphocytes in high endothelial venules (HEV), which precedes migration across the vessel wall into the lymph node. L-selectin is cleaved by proteolysis in the membrane proximal region, but the physiological role of this shedding is unclear. Studies using hydroxamate-based metalloproteinase inhibitors have implicated metalloproteinase(s) in L-selectin shedding and lymphoid cells lacking in the metalloproteinase TACE (ADAM 17) fail to shed L-selectin, suggesting that it is directly or indirectly involved in cleavage. Knockout mice in which the catalytic domain of TACE has been targeted (taceZn/Zn) die in utero. To study the role of TACE in leucocytes, irradiated mice were used as hosts for reconstitution with taceZn/Zn or wild type (WT) foetal liver stem cells. Phenotypic analysis of the reconstituted chimeric mice determined that there was no significant effect of the TACE mutation on the proportions of cell subsets in the lymph nodes or thymus. The taceZn/Zn chimeric spleen was found to be significantly larger than that of mice reconstituted with WT cells and, on further analysis, was shown to have a higher proportion of large granular cells (36% of total cells) in comparison to WT (19%). A higher proportion of large granular cells was also seen in taceZn/Zn chimeric bone marrow (70% vs. 59%). Increased L-selectin expression was seen on taceZn/Zn B lymphocytes and non-neutrophil myeloid cells in the bone marrow, and on taceZn/Zn on neutrophils in the spleen. PMA stimulation of blood lymphocytes and splenocytes confirmed that taceZn/Zn T and B lymphocytes are unable to shed L-selectin. However, taceZn/Zn peripheral lymph node T lymphocytes undergo constitutive basal shedding in vitro suggesting a TACE independent shedding pathway in these cells. TACE independent shedding was confirmed by the presence of wild type levels of soluble L-selectin in the sera of L-selectin-/- mice reconstituted with taceZn/Zn foetal liver cells. taceZn/Zn cells migrated normally through a cultured high endothelial cell (HEC) monolayer and down-regulated L-selectin upon adhesion to HEC. There was no effect of the TACE mutation on lymphocyte trafficking into peripheral lymph nodes in vivo. We conclude that TACE is not the only enzyme responsible for L-selectin cleavage in T lymphocytes and, that TACE does not regulate lymphocyte interactions with HEC during migration into peripheral lymph nodes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available