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Defective T-lymphocyte signal transduction and function in leukocyte adhesion deficiency
L M Voss1, R T Abraham, K H Rhodes
1Department of Pediatrics, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
Insights
This study investigated the role of lymphocyte function-associated antigen-1 (LFA-1) in T cell activation. T cells lacking LFA-1 showed defects in signaling, lymphokine secretion, and cytotoxicity, suggesting LFA-1 is crucial for T cell function.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Lymphocyte function-associated antigen-1 (LFA-1) is a cell surface protein mediating cellular adhesion.
- Its role in transmembrane signaling and regulation of cellular functions remains unclear.
- Previous studies were limited by LFA-1's ubiquitous expression and assay challenges.
Purpose of the Study:
- To investigate the involvement of LFA-1 in transmembrane signaling and T cell activation.
- To overcome limitations of previous studies by using T cells from a patient with leukocyte adhesion deficiency (LAD).
Main Methods:
- Isolated and cloned T lymphocytes from a patient with LAD (LFA-1-deficient).
- Stimulated T-cell lines (LAD and normal) via their T-cell antigen receptor.
- Assessed transmembrane signaling (phosphoinositide turnover), lymphokine secretion (lymphotoxin), and cytotoxicity.
Main Results:
- T-cell lines from the LAD patient were intrinsically defective in phosphoinositide turnover.
- LAD T cells exhibited impaired lymphotoxin secretion.
- Cytotoxicity mediated by LAD T cells was significantly reduced.
Conclusions:
- LFA-1 plays a critical role in T cell activation beyond adhesion.
- LFA-1 is essential for effective transmembrane signaling, lymphokine secretion, and cytotoxicity.
- Defective LFA-1 expression leads to intrinsic T cell activation defects.
Abstract:
The lymphocyte function-associated antigen-1 (LFA-1) molecule is a cell surface heterodimeric protein that directly mediates cellular adhesion. However, it remains unclear whether LFA-1 molecules are also involved in transmembrane signaling and in the subsequent regulation of cellular functions. Previous attempts to evaluate this issue have been hampered by (1) the ubiquitous expression of LFA-1 on normal lymphoid cells, (2) the limited availability of assays for cellular activation that are not affected by cellular adhesion, and (3) the difficulties in interpreting studies where anti-LFA-1 mAbs are used to alternatively block or stimulate this antigen. In order to avoid these pitfalls, we first isolated and cloned T lymphocytes from a patient with leukocyte adhesion deficiency (LAD), an inherited disorder in which the defective expression of leukocyte integrins results in the production of LFA-1- T lymphocytes. Different T-cell lines from this patient and from normal individuals were then stimulated through their T-cell antigen receptor complex and were then tested for three aspects of cellular activation: (1) transmembrane signaling (i.e., phosphoinositide turnover), (2) lymphokine secretion (i.e., release of lymphotoxin), and (3) their capacity to mediate cellular cytotoxicity (using murine anti-CD3-producing hybridoma cells as targets). Using assay systems that did not involve LFA-1-mediated adhesion to antigen-presenting cells or target cells, the T-cell lines from the LAD patient were found to be intrinsically defective in all three of these parameters of T cell activation.(ABSTRACT TRUNCATED AT 250 WORDS)