Superantigen-Induced T Cell:B Cell Conjugation Is Mediated by LFA-1 and Requires Signaling Through Lck, But Not ZAP-70

The formation of a conjugate between a T cell and an APC requires the activation of integrins on the T cell surface and remodeling of cytoskeletal elements at the cell-cell contact site via inside-out signaling. The early events in this signaling pathway are not well understood, and may differ from...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2001-11, Vol.167 (10), p.5708-5718
Main Authors: Morgan, Margaret M, Labno, Christine M, Van Seventer, Gijs A, Denny, Michael F, Straus, David B, Burkhardt, Janis K
Format: Article
Language:English
Subjects:
B-Lymphocytes - immunology
Cell Adhesion
Cell Line
Cytoskeleton - metabolism
Enzyme Inhibitors - pharmacology
Humans
Jurkat Cells
Lck protein
LFA-1 antigen
Lymphocyte Function-Associated Antigen-1 - physiology
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - physiology
MAP Kinase Signaling System - drug effects
Mitogen-Activated Protein Kinase Kinases - physiology
Mutation
Protein Kinase C - antagonists & inhibitors
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - physiology
Signal Transduction
Superantigens - immunology
T-Lymphocytes - immunology
Type C Phospholipases - antagonists & inhibitors
ZAP-70 protein
ZAP-70 Protein-Tyrosine Kinase
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Summary:The formation of a conjugate between a T cell and an APC requires the activation of integrins on the T cell surface and remodeling of cytoskeletal elements at the cell-cell contact site via inside-out signaling. The early events in this signaling pathway are not well understood, and may differ from the events involved in adhesion to immobilized ligands. We find that conjugate formation between Jurkat T cells and EBV-B cells presenting superantigen is mediated by LFA-1 and absolutely requires Lck. Mutations in the Lck kinase, Src homology 2 or 3 domains, or the myristoylation site all inhibit conjugation to background levels, and adhesion cannot be restored by the expression of Fyn. However, ZAP-70-deficient cells conjugate normally, indicating that Lck is required for LFA-1-dependent adhesion via other downstream pathways. Several drugs that inhibit T cell adhesion to ICAM-1 immobilized on plastic, including inhibitors of mitogen-activated protein/extracellular signal-related kinase kinase, phosphatidylinositol-3 kinase, and calpain, do not inhibit conjugation. Inhibitors of phospholipase C and protein kinase C block conjugation of both wild-type and ZAP-70-deficient cells, suggesting that a phospholipase C that does not depend on ZAP-70 for its activation is involved. These results are not restricted to Jurkat T cells; Ag-specific primary T cell blasts behave similarly. Although the way in which Lck signals to enhance LFA-1-dependent adhesion is not clear, we find that cells lacking functional Lck fail to recruit F-actin and LFA-1 to the T cell:APC contact site, whereas ZAP-70-deficient cells show a milder phenotype characterized by disorganized actin and LFA-1 at the contact site.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.167.10.5708