Mechanisms of pertussis toxin inhibition of lymphocyte-HEV interactions. I. Analysis of lymphocyte homing receptor-mediated binding mechanisms.
The molecular mechanisms by which pertussis toxin (PTX) inhibits lymphocyte homing to peripheral lymph nodes (PLN) remain poorly understood. PTX-treated lymphocytes express homing receptors, yet cannot extravasate into PLN in vivo. Methylation of PTX, a procedure known to inactivate the B-oligomer of the toxin, restored high endothelial venule (HEV) binding capacity. In vitro studies established that toxin exposure inhibited the accessory role of LFA-1 in HEV binding. In contrast, PTX-exposed lymphocytes exhibited normal MEL-14-mediated HEV binding. Analysis of membrane fluidity revealed a 20% decrease in fluorescence polarization in PTX-exposed lymphocytes. On the basis of the current experiments, we propose a "zipper" model of lymphocyte-HEV interaction, in which lateral mobility of adhesion receptors in the cell membrane toward a site of endothelial contact is necessary to maintain adhesion against the shear force due to blood flow. PTX inhibits these processes by decreasing membrane fluidity, and by altering accessory adhesion molecule function.
Steen
P D
PD
University of Utah/VAMC Cancer Immunotherapy Program, Salt Lake City.
Ashwood
E R
ER
Huang
K
K
Daynes
R A
RA
Chung
H T
HT
Samlowski
W E
WE
D000818:Animals; D001562:Benzimidazoles; D002465:Cell Movement / Q000187:drug effects; D004729:Endothelium, Lymphatic / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D005856:Germ-Free Life; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology; D008214:Lymphocytes / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D037342:Pertussis Toxin; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis / Q000378:metabolism*; D013329:Structure-Activity Relationship; D010566:Virulence Factors, Bordetella / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D001562:Benzimidazoles; D005456:Fluorescent Dyes; D016169:Lymphocyte Function-Associated Antigen-1; D016201:Receptors, Lymphocyte Homing; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; C017807:bisbenzimide ethoxide trihydrochloride