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Published on: June 13, 2014
Expression and function of lymphocyte function associated antigen-3 (LFA-3) at the blood-brain barrier
1Department of Pathology and Laboratory Medicine, Vancouver General Hospital, British Columbia, Canada.
Insights
Lymphocyte function associated antigen-3 (LFA-3) is expressed on human brain endothelial cells and supports T-cell proliferation. This suggests a role for LFA-3 in initiating central nervous system inflammation.
Area of Science:
- Neuroimmunology
- Endothelial Cell Biology
- Immunology
Background:
- Lymphocyte function associated antigen-3 (LFA-3) is a cell surface glycoprotein crucial for T-cell activation and proliferation.
- The blood-brain barrier (BBB) plays a critical role in regulating immune cell entry into the central nervous system (CNS).
Purpose of the Study:
- To investigate the expression and function of LFA-3 at the BBB using an in vitro model.
- To determine the role of LFA-3 in T-cell interactions with human brain microvessel endothelial cells (HBMEC).
Main Methods:
- Primary cultures of HBMEC were used to model the BBB.
- LFA-3 surface expression was assessed using immunogold silver staining.
- LFA-3 RNA presence was confirmed via reverse transcriptase-polymerase chain reaction (RT-PCR).
- T-cell proliferation assays were conducted with purified CD4+ T-lymphocytes incubated with HBMEC monolayers.
Main Results:
- Unstimulated HBMEC constitutively express LFA-3 on their surface and possess LFA-3 RNA.
- LFA-3 expression showed only marginal upregulation upon stimulation with TNF-alpha or IFN-gamma.
- Incubation with HBMEC significantly increased the proliferation of alpha-CD3 activated CD4+ T-cells.
- Monoclonal antibodies targeting LFA-3 blocked T-cell proliferation by 64-76%.
Conclusions:
- Cerebral endothelial cells express LFA-3 and can provide costimulatory signals for T-cell activation and proliferation.
- The expression of LFA-3 by the BBB suggests its involvement in initiating inflammatory responses within the human CNS.
Abstract:
Lymphocyte function associated antigen-3 (LFA-3) is a cell surface glycoprotein involved in antigen independent T-cell activation and proliferation. The expression and function of LFA-3 at the blood-brain barrier were studied in an in vitro model consisting of primary cultures of human brain microvessel endothelial cells (HBMEC). Surface expression of LFA-3 was detected by immunogold silver staining and the presence of RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). Unstimulated HBMEC in primary culture constitutively express LFA-3 on their surface. Expression is only marginally upregulated following stimulation with tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma). Similarly, LFA-3 RNA is present constitutively in unstimulated HBMEC with minimal increase after co-incubation with TNF-alpha and IFN-gamma. The function of LFA-3 as a costimulatory molecule on HBMEC was investigated by incubating purified CD4+ T-lymphocytes with resting or IFN-gamma treated HBMEC monolayers. Proliferation of alpha-CD3 activated CD4+ T-cells was significantly increased upon incubation with resting or activated endothelial cells. Monoclonal antibodies to LFA-3 consistently blocked the proliferative response by 64-76%. The ability of the cerebral endothelium to express LFA-3 and provide secondary signals for T-cell proliferation suggests that cerebral EC may be important in the initiation of inflammatory responses in the human central nervous system.
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