ISSN:
1573-2592
Keywords:
Leukocyte adhesion deficiency
;
lymphocyte function-associated antigen-1
;
T lymphocytes
;
signal transduction
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
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., phospho-inositide 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. However, the defects in transmembrane signaling and lymphokine secretion were relative rather than absolute, as the cells were fully responsive to the maximal receptor stimuli provided by immobilized anti-CD3 mAbs or phytohemagglutinin. Our findings suggest that the leukocyte integrins act not only as cellular adhesion molecules, but also directly affect transmembrane signaling during T-cell activation.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00917423
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