Siegelman M H, Stanescu D, Estess P
Laboratory of Molecular Pathology, Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
J Clin Invest. 2000 Mar;105(5):683-91. doi: 10.1172/JCI8692.
Leukocytes extravasate from the blood in response to physiologic or pathologic demands by means of complementary ligand interactions between leukocytes and endothelial cells. The multistep model of leukocyte extravasation involves an initial transient interaction ("rolling" adhesion), followed by secondary (firm) adhesion. We recently showed that binding of CD44 on activated T lymphocytes to endothelial hyaluronan (HA) mediates a primary adhesive interaction under shear stress, permitting extravasation at sites of inflammation. The mechanism for subsequent firm adhesion has not been elucidated. Here we demonstrate that the integrin VLA-4 is used in secondary adhesion after CD44-mediated primary adhesion of human and mouse T cells in vitro, and by mouse T cells in an in vivo model. We show that clonal cell lines and polyclonally activated normal T cells roll under physiologic shear forces on hyaluronate and require VCAM-1, but not ICAM-1, as ligand for subsequent firm adhesion. This firm adhesion is also VLA-4 dependent, as shown by antibody inhibition. Moreover, in vivo short-term homing experiments in a model dependent on CD44 and HA demonstrate that superantigen-activated T cells require VLA-4, but not LFA-1, for entry into an inflamed peritoneal site. Thus, extravasation of activated T cells initiated by CD44 binding to HA depends upon VLA-4-mediated firm adhesion, which may explain the frequent association of these adhesion receptors with diverse chronic inflammatory processes.
白细胞通过白细胞与内皮细胞之间互补的配体相互作用，响应生理或病理需求从血液中渗出。白细胞渗出的多步骤模型包括初始的短暂相互作用（“滚动”黏附），随后是次级（牢固）黏附。我们最近发现，活化T淋巴细胞上的CD44与内皮透明质酸（HA）结合，在剪切应力下介导初级黏附相互作用，从而允许在炎症部位渗出。后续牢固黏附的机制尚未阐明。在此我们证明，整合素VLA-4在体外人及小鼠T细胞以及体内模型中小鼠T细胞的CD44介导的初级黏附之后用于次级黏附。我们发现，克隆细胞系和多克隆活化的正常T细胞在生理剪切力下在透明质酸盐上滚动，并且需要VCAM-1而非ICAM-1作为后续牢固黏附的配体。如抗体抑制所示，这种牢固黏附也依赖于VLA-4。此外，在依赖CD44和HA的模型中的体内短期归巢实验表明，超抗原活化的T细胞进入炎症腹膜部位需要VLA-4而非LFA-1。因此，由CD44与HA结合引发的活化T细胞渗出取决于VLA-4介导的牢固黏附，这可能解释了这些黏附受体与多种慢性炎症过程的频繁关联。
