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R. Aaron Warnock^*, Sanaz Askari, Eugene C. Butcher^*, and Ulrich H. von Andrian

From the ^* Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University, Stanford, California 94305, and the Veterans Affairs Palo Alto Health Care Systems, Palo Alto, California 94304; and The Center for Blood Research and the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

To characterize the adhesion cascade that directs lymphocyte homing to peripheral lymph nodes (PLNs), we investigated the molecular mechanisms of lymphocyte interactions with the microvasculature of subiliac lymph nodes. We found that endogenous white blood cells and adoptively transferred lymph node lymphocytes (LNCs) tethered and rolled in postcapillary high endothelial venules (HEVs) and to a lesser extent in collecting venules. Similarly, firm arrest occurred nearly exclusively in the paracortical HEVs. Endogenous polymorphonuclear (PMNs) and mononuclear leukocytes (MNLs) attached and rolled in HEVs at similar frequencies, but only MNLs arrested suggesting that the events downstream of primary rolling interactions critically determine the specificity of lymphocyte recruitment. Antibody inhibition studies revealed that L-selectin was responsible for attachment and rolling of LNCs, and that LFA-1 was essential for sticking. LFA-1–dependent arrest was also abolished by pertussis toxin, implicating a requirement for G_i–-protein–linked signaling. 4 integrins, which play a critical role in lymphocyte homing to Peyer's Patches, made no significant contribution to attachment, rolling, or sticking in resting PLNs. Velocity analysis of interacting LNCs revealed no detectable contribution by LFA-1 to rolling. Taken together, our results suggest that lymphocyte– HEV interactions within PLNs are almost exclusively initiated by L-selectin followed by a G protein–coupled lymphocyte-specific activation event and activation-induced engagement of LFA-1. These events constitute a unique adhesion cascade that dictates the specificity of lymphocyte homing to PLNs.

¹ Abbreviations used in this paper: BCECF, 2'7',-bis-(2-carboxyethyl)-5(and 6) carboxyfluorescein; cRPMI, RPMI 1640 + 10% bovine calf serum; HEV, high endothelial venule; LNC, lymph node lymphocyte; MLN, mesenteric lymph node; MNL, mononuclear lymphocyte; MTX, mutant pertussis toxin; PP, Peyer's patch; PLN, peripheral lymph nodes; PNAd, peripheral node addressin; PTX, pertussis toxin; V_blood, mean blood flow velocity; V_fast, mean fast cell velocity; V_rel, relative rolling velocity; V_roll, rolling velocity; WBC, white blood cell.

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