MOLECULAR MECHANISMS OF LYMPHOCYTE HOMING TO PERIPHERAL LYMPH-NODES

To characterize the adhesion cascade that directs lymphocyte homing to peripheral lymph nodes (PLNs), we investigated the molecular mechanis ms of lymphocyte interactions with the microvasculature of subiliac ly mph nodes. We found that endogenous white blood cells and adoptively t ransferred lymph node lymphocytes (LNCs) tethered and rolled in postca pillary high endothelial venules (HEVs) and to a lesser extent in coll ecting venules. Similarly, firm arrest occurred nearly exclusively in die paracortical HEVs. Endogenous polymorphonuclear (PMNs) and mononuc lear leukocytes (MNLs) attached and rolled in HEVs at similar frequenc ies, but only MNLs arrested suggesting that the events downstream of p rimary rolling interactions critically determine the specificity of ly mphocyte recruitment. Antibody inhibition studies revealed that L-sele ctin was responsible for attachment and rolling of LNCs, and that LFA- 1 was essential for sticking, LFA-1-dependent arrest was also abolishe d by pertussis toxin, implicating a requirement for G alpha(i-)-protei n-linked signaling. alpha 4 integrins, which play a critical role in l ymphocyte homing to Peyer's Patches, made no significant contribution to attachment, rolling, or sticking in resting PLNs. Velocity analysis of interacting LNCs revealed Ilo detectable contribution by LFA-1 to rolling. Taken together, our results suggest that lymphocyte-HEV inter actions within PLNs are almost exclusively initiated by L-selectin fol lowed by a G protein-coupled lymphocyte-specific activation event and activation-induced engagement of LFA-1. These events constitute a uniq ue adhesion cascade that dictates the specificity of lymphocyte homing to PLNs.