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Membranal Cholesterol Is Not Required for L-Selectin Adhesiveness in Primary Lymphocytes but Controls a Chemokine-Induced Destabilization of L-Selectin Rolling Adhesions¹

Oren Dwir^*, Valentin Grabovsky^*, Ronit Pasvolsky^*, Eugenia Manevich^*, Revital Shamri^*, Paul Gutwein, Sara W. Feigelson^*, Peter Altevogt and Ronen Alon^2,*

^* Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; and Tumor Immunology Programme, Cancer Research Center, Heidelberg, Germany

Cholesterol-enriched lipid microdomains regulate L-selectin signaling, but the role of membrane cholesterol in L-selectin adhesion is unclear. Arrest chemokines are a subset of endothelial chemokines that rapidly activate leukocyte integrin adhesiveness under shear flow. In the absence of integrin ligands, these chemokines destabilize L-selectin-mediated leukocyte rolling. In the present study, we investigated how cholesterol extraction from the plasma membrane of peripheral blood T or B cells affects L-selectin adhesions and their destabilization by arrest chemokines. Unlike the Jurkat T cell line, whose L-selectin-mediated adhesion is cholesterol dependent, in primary human PBLs and in murine B cells and B cell lines, cholesterol depletion did not impair any intrinsic adhesiveness of L-selectin, consistent with low selectin partitioning into lipid rafts in these cells. However, cholesterol raft disruption impaired the ability of two arrest chemokines, CXCL12 and CXCL13, but not of a third arrest chemokine, CCL21, to destabilize L-selectin-mediated rolling of T lymphocytes. Actin capping by brief incubation with cytochalasin D impaired the ability of all three chemokines to destabilize L-selectin rolling. Blocking of the actin regulatory phosphatidylinositol lipid, phosphatidylinositol 4,5-bisphosphate, did not affect chemokine-mediated destabilization of L-selectin adhesions. Collectively, our results suggest that L-selectin adhesions are inhibited by actin-associated, cholesterol-stabilized assemblies of CXCL12- and CXCL13-binding receptors on both T and B lymphocytes. Thus, the regulation of L-selectin by cholesterol-enriched microdomains varies with the cell type as well as with the identity of the destabilizing chemokine.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Israel Science Foundation and by the Minerva Foundation, Germany. R.A. is the Incumbent of the Linda Jacobs Chair in Immune and Stem Cell Research.

² Address correspondence and reprint requests to Dr. Ronen Alon, Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. E-mail address: ronen.alon{at}weizmann.ac.il

³ Abbreviations used in this paper: ERM, Ezrin/Radixin/Moesin; GPCR, G protein-coupled receptor; MCD, methyl- cyclodextrin; PIP₂, phosphatidylinositol 4,5-bisphosphate; PNAd, peripheral node addressin.

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