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Static Adhesion Assay for the Study of Integrin Activation in T Lymphocytes
Published on: June 13, 2014
Mechanisms for induction of L-selectin loss from T lymphocytes by a cryptococcal polysaccharide, glucuronoxylomannan
Z M Dong1, L Jackson, J W Murphy
1Department of Microbiology and Immunology, University of Oklahoma Health Science Center, Oklahoma City 73190, USA.
Abstract:
Disseminated cryptococcosis is accompanied by cryptococcal polysaccharides in the serum and the lack of cellular infiltrates in infected tissues. Cryptococcal polysaccharides given intravenously to mice inhibit the influx of T lymphocytes into the sites of cell-mediated immune response. The focus here was to determine whether cryptococcal polysaccharides modulate the expression of molecules, such as L-selectin, that are important in extravasation of T cells. Cryptococcal glucuronoxylomannan (GXM), but not galactoxylomannan or mannoprotein, was found to cause loss of L-selectin from freshly isolated human T cells of both CD4 and CD8 subsets and from Jurkat cells. With the signaling-pathway inhibitors staurosporine (which inhibits protein kinase C) and herbimycin A (which inhibits protein tyrosine kinases), we showed that GXM or the cryptococcal culture filtrate antigen CneF directly induces L-selectin loss from CD4(+) and CD8(+) T cells via a herbimycin A-sensitive pathway(s) presumably involving one or more protein tyrosine kinases but not via a pathway involving protein kinase C. Loss of L-selectin from the T cells before the T cells have a chance to bind to L-selectin ligands on endothelial cells would be expected to prevent T-cell migration into inflamed tissues and/or lymph organs.
Insights
Cryptococcal glucuronoxylomannan (GXM) causes T cells to lose L-selectin, a molecule crucial for migration. This finding explains how cryptococcosis hinders immune responses by preventing T cells from reaching infected tissues.
Area of Science:
- Immunology
- Molecular Biology
- Microbiology
Background:
- Disseminated cryptococcosis is characterized by fungal polysaccharides and a lack of immune cell infiltration.
- Cryptococcal polysaccharides are known to inhibit T lymphocyte influx into sites of cell-mediated immunity.
- The mechanism by which T cell migration is inhibited during cryptococcosis remains incompletely understood.
Purpose of the Study:
- To investigate whether cryptococcal polysaccharides modulate L-selectin expression on T cells.
- To determine the specific cryptococcal polysaccharide responsible for altering T cell extravasation molecules.
- To elucidate the signaling pathways involved in GXM-induced L-selectin modulation.
Main Methods:
- Isolated human T cells (CD4+ and CD8+ subsets) and Jurkat cells were treated with cryptococcal polysaccharides.
- Flow cytometry was used to assess L-selectin expression on T cells.
- Signaling pathway inhibitors (staurosporine and herbimycin A) were employed to identify the molecular mechanisms involved.
Main Results:
- Cryptococcal glucuronoxylomannan (GXM) significantly reduced L-selectin expression on both CD4+ and CD8+ T cells.
- Galactoxylomannan and mannoprotein did not induce L-selectin loss.
- GXM-induced L-selectin loss was sensitive to herbimycin A, suggesting involvement of protein tyrosine kinases, but not protein kinase C.
Conclusions:
- GXM directly induces L-selectin loss from T cells via a protein tyrosine kinase-dependent pathway.
- This GXM-mediated downregulation of L-selectin likely impairs T cell migration to infected tissues.
- The findings provide a molecular explanation for the impaired cellular immunity observed in disseminated cryptococcosis.
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