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Thrombospondin 1, an autocrine regulator in T cell adhesion and migration
Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Immunology.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lymphocytes, the principal cells of the immune system, perform the immune function throughout the body by their unique capacity to circulate in blood stream and lymphatic vessels and migrate in lymphoid and non-lymphoid tissues. The mechanisms regulating lymphocyte adhesion and migration, interactions with cells and components within the extracellular matrix are not fully understood. The aim of this work has been to elucidate molecular mechanisms governing T lymphocyte adhesion and migration by endogenous molecules.

The studies presented in this thesis have shown that thrombospondin-1 (TSP-1) is expressed in T lymphocytes with a high turnover, manifested by variable cell surface expression, and is regulated by SDF-1a, adhesion to fibronectin and collagen type IV. The TSP-1 binding site of calreticulin (CRT), spanning amino acid 19-32, was shown to be a major triggering factor for T cell migration within a three-dimensional collagen type 1 matrix. The chemokine SDF-1a stimulated migration via a calreticulin-TSP-1 pathway. Endogenous calreticulin binding to the N-terminal domain of endogenous TSP-1 elicited a motogenic signal to the T cells through the C-terminal domain of TSP-1 and its cell surface receptor integrin-associated protein (IAP, CD47). Inhibition experiments of ligand binding of CD91 by receptor associated protein (RAP) and small interfering RNA technology indicated that CD91 is an important factor in TSP-1-mediated T cell adhesion and migration. These results unveil an autocrine mechanism of CRT-TSP-1-CD47-CD91 interaction for the control of T cell motility and migration within 3D extracellular matrix substrata.

The data demonstrated that T cell adhesion and migration are sequential events governed by a series of interacting cell surface molecules comprising a CRT-TSP-1-CD47-CD91 pathway where endogenous TSP-1 functions as the hub. Ligation of the CD3/T cell antigen receptor complex determines T cell adhesion through this mechanism. CRT interaction with the N-terminal domain of TSP-1 elicits cytoplasmic spreading, and augments adhesion, while a counter-adhesive motogenic pathway, triggering interaction of the C-terminal domain of TSP-1, induces migration. CD91-dependent internalization of TSP-1 is a crucial event of this motogenic pathway.

In conclusion, the studies provide a novel mechanism governing T cell adhesion and migration within extracellular matrix substrata.

Place, publisher, year, edition, pages
Umeå: Klinisk mikrobiologi , 2005. , 59 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; No. 984-0346-6612
Keyword [en]
Immunology, T cell, adhesion, migration, thrombospondin
Keyword [sv]
Immunologi
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-599ISBN: 91-7305-830-0 (print)OAI: oai:DiVA.org:umu-599DiVA: diva2:143924
Public defence
2005-10-24, E04, NUS by 6 E, 13:00 (English)
Opponent
Supervisors
Available from: 2005-09-23 Created: 2005-09-23 Last updated: 2009-11-20Bibliographically approved
List of papers
1. T lymphocyte expression of thrombospondin-1 and adhesion to extracellular matrix components.
Open this publication in new window or tab >>T lymphocyte expression of thrombospondin-1 and adhesion to extracellular matrix components.
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2002 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 32, no 4, 1069-1079 p.Article in journal (Refereed) Published
Abstract [en]

The mechanisms controlling the formation of pseudopodia and other active cell edges in T lymphocytes are not understood. We show here that T lymphocytes express thrombospondin-1 (TSP-1). TSP-1 in T lymphocytes has a high turnover as shown by the fact that brefeldin and monensin rapidly increase while cycloheximide tend to decrease the cellular TSP-1 content. T cell TSP-1 is preferentially stored intracellularly and shows variable cell surface expression. T lymphocyte adhesion to fibronectin and collagen type IV induces TSP-1 expression on the cell surface via a brefeldin sensitive mechanism. A monoclonal antibody to TSP-1 inhibits the flattening and pseudopodia formation of the adherent T cells. Furthermore, the same antibody to TSP-1 also exerts an inhibitory effect on T cell migration in the absence of exogenous TSP-1. These results indicate that endogenous TSP-1 is part of an adhesion-dependent mechanism controlling cytoplasmic spreading and migration in T lymphocytes.

Identifiers
urn:nbn:se:umu:diva-27748 (URN)10.1002/1521-4141(200204)32:4<1069::AID-IMMU1069>3.0.CO;2-E (DOI)11920574 (PubMedID)
Available from: 2009-11-18 Created: 2009-11-18 Last updated: 2017-12-12
2. Autocrine regulation of T cell motility by calreticulin-thrombospondin-1 interaction
Open this publication in new window or tab >>Autocrine regulation of T cell motility by calreticulin-thrombospondin-1 interaction
2005 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 174, no 2, 654-661 p.Article in journal (Refereed) Published
Abstract [en]

The mechanisms regulating T lymphocyte migration within the extracellular matrix are not understood. We show in this study that the thrombospondin-1 binding site of calreticulin, spanning aa 19-32, is a major triggering factor for T cell motility and migration within a three-dimensional collagen type 1 matrix, and that exogenous motogenic factors such as chemokines can stimulate migration via a calreticulin-thrombospondin-1 pathway. Endogenous calreticulin binding to the N-terminal domain of endogenous thrombospondin-1 elicited a motogenic signal to the T cells through the C-terminal domain of thrombospondin-1 and its cell surface receptor integrin-associated protein (CD47). Our data further revealed that thrombospondin-1 was expressed on the cell surface with a high turnover, and that PI3K and the Janus family of tyrosine kinases were required for T cell motility mediated through calreticulin, thrombospondin-1, and CD47. These results unveil an autocrine mechanism of calreticulin-thrombospondin-1-CD47 interaction for the control of T cell motility and migration within three-dimensional extracellular matrix substrata.

Identifiers
urn:nbn:se:umu:diva-4707 (URN)15634883 (PubMedID)
Available from: 2005-09-23 Created: 2005-09-23 Last updated: 2017-12-14Bibliographically approved
3. Lymphocyte adhesion controlled by an endogenous calreticulin-thrombospondin-1-CD47-CD91 pathway
Open this publication in new window or tab >>Lymphocyte adhesion controlled by an endogenous calreticulin-thrombospondin-1-CD47-CD91 pathway
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:umu:diva-4708 (URN)
Available from: 2005-09-23 Created: 2005-09-23Bibliographically approved
4. Long-term gene silencing by small interfering RNA in mammalian cells: Establishment of a dual-promoter lentivirus delivery system
Open this publication in new window or tab >>Long-term gene silencing by small interfering RNA in mammalian cells: Establishment of a dual-promoter lentivirus delivery system
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4709 (URN)
Available from: 2005-09-23 Created: 2005-09-23 Last updated: 2010-01-13Bibliographically approved

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