Effects of cellular activation on lymphocyte recirculation

Circulating lymphocytes emigrate from the blood into most secondary lymphoid organs by selective adherence to specialized vascular structures, termed high endothelial venules (HEV), and subsequent active translocation. Besides lymphocyte-HEV recognition and adhesion, which depends on productive interactions between the organ specific lymphocyte homing receptors and the vascular addressins, lymphocytes must possess the capacity to physically penetrate and traverse the endothelium. It has been known that resting and activated lymphocytes exhibit distinct homing patterns, yet the mechanisms responsible for controlling their migration are not fully elucidated. Exposure of murine lymphocytes to pertussis toxin or phorbol esters before they are transfused into normal syngeneic hosts markedly depress their ability to localize into lymph nodes and Peyer's patches. Mechanisms responsible for the altered homing behavior of these lymphocytes were investigated here. Pertussis toxin-treated lymphocytes were found to express normal levels of peripheral lymph node-specific homing receptor (MEL-14 receptor) and be able to attach to peripheral lymph node HEV. In contrast, phorbol ester-induced protein kinase C activation of lymphocytes caused a marked reduction in phenotypic and functional expression of the MEL-14 receptor. The loss of MEL-14 receptor expression was due to a rapid shedding of the receptor from the activated lymphocytes. Although localization of phorbol ester-treated lymphocytes into Peyer's patches is inhibited, normal levels of Peyer's patch HEV-specific homing receptor were expressed by these cells. Therefore, modulation of the surface expression of lymphocyte homing receptors comprises one of the mechanisms that regulate the homing of activated lymphocytes. However homing receptor expression is insufficient to support lymphocyte extravasation. The finding that PKC activation of lymphocytes changes their homing behavior and their surface expression of MEL-14 receptor provides a new system for studying the recirculation of activated lymphocytes, and a basis for further experimentation to investigate the molecular mechanisms which mediate the release of the MEL-14 receptor by activated lymphocytes. The observation that the MEL-14 receptor and the Peyer's patch HEV-specific homing receptor are differentially regulated by activated lymphocytes also provide useful information for identifying new receptors with other specificities. The physiological relevance of the downregulation of MEL-14 receptor and differential regulation of distinct homing receptors to the immune functions of activated lymphocytes await to be determined.