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The Leukocyte Integrin _Dß₂ Binds VCAM-1: Evidence for a Binding Interface Between I Domain and VCAM-1

Monica Van der Vieren^*, David T. Crowe^*, Denise Hoekstra^*, Rosemay Vazeux^*, Patricia A. Hoffman^*, Mitchell H. Grayson, Bruce S. Bochner, W. Michael Gallatin^* and Donald E. Staunton^1,*

^* ICOS Corp., Bothell, WA 98021; and Department of Medicine, Division of Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21218

The trafficking of leukocytes through tissues is supported by an interaction between the ß₂ (CD18) integrins CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) and their ligand ICAM-1. The most recently identified and fourth member of the ß₂ integrins, _Dß₂, selectively binds ICAM-3 and does not appear to bind ICAM-1. We have reported recently that _Dß₂ can support eosinophil adhesion to VCAM-1. Here we demonstrate that expression of _Dß₂ in a lymphoid cell that does not express ₄ integrins confers efficient binding to VCAM-1. In addition, a soluble form of _Dß₂ binds VCAM-1 with greater efficiency relative to ICAM-3. The I domain of D contains a binding site for VCAM-1 since recombinant _D I domain binds specifically to VCAM-1. In addition, _D mAb that block cellular binding to VCAM-1 bind the _D I domain. Using VCAM-1 mutants we have determined that the binding site on VCAM-1 for _Dß₂ overlaps with that of ₄ integrins. Substitution of VCAM-1 aspartate at position 40, D40, within the conserved integrin binding site, diminishes binding to _Dß₂ and abrogates binding to the _D I domain. The corresponding integrin binding site residue in ICAM-3 is also essential to _Dß₂ binding. Finally, we demonstrate that _Dß₂ can support lymphoid cell adhesion to VCAM-1 under flow conditions at levels equivalent to those mediated by ₄ß₁. These results indicate that VCAM-1 can bind to an I domain and that the binding of _Dß₂ to VCAM-1 may contribute to the trafficking of a subpopulation of leukocytes that express _Dß₂.

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