α4 integrins mediate lymphocyte attachment and rolling under physiologic flow

TLDR

Selectins are the only adhesion receptors known to initiate leukocyte interaction under physiological shear, while beta‑2 integrins require prior selectin-mediated rolling to engage. Alpha‑4 integrins, especially alpha‑4β7, can initiate lymphocyte tethering, rolling, and arrest under shear without selectin involvement, concentrating on microvilli to enable L‑selectin–independent attachment in vivo, whereas beta‑2 integrins cannot.

Abstract

Of the several families of adhesion receptors involved in leukocyte-endothelial cell interactions, only the selectins have been shown to initiate leukocyte interaction under physiologic shear; indeed, beta 2 (CD18) intergrins responsible for neutrophil arrest are unable to engage without prior selectin-mediated rolling. In contrast, alpha 4 (CD49d) integrins are shown here to initiate lymphocyte contract ("tethering") in vitro under shear and in the absence of a selectin contribution. The alpha 4 integrin ligands MAdCAM-1 and VCAM-1 support loose reversible interactions including rolling, as well as rapid sticking and arrest that is favored following integrin activation. Moreover, alpha 4 beta 7 mediates L-selectin (CD62L)-independent attachment of blood-borne lymphocytes to lamina propria venules in situ. Scanning electron microscopy of alpha 4 beta 7hi lymphoid cells reveals that, like L-selectin, alpha 4 beta 7 is highly concentrated on microvillous sites of initial cellular contact, whereas the beta 2 integrin LFA-1 is excluded from villi. Thus, alpha 4 but not beta 2 integrins can initiate leukocyte adhesion under flow, a capacity that may be in part a function of topographic presentation on microvilli.