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The Functional Interaction of the ₂ Integrin Lymphocyte Function-Associated Antigen-1 with Junctional Adhesion Molecule-A Is Mediated by the I Domain^{1 ,2}

Line Fraemohs^*, Rory R. Koenen^3,*, Georg Ostermann^3,*, Bo Heinemann and Christian Weber^4,*

^* Department of Molecular Cardiovascular Research, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany; and Revotar Biopharmaceuticals AG, Hennigsdorf, Germany

Binding of the ₂ integrin LFA-1 (_L2) to junctional adhesion molecule-A (JAM-A) has been shown to enhance leukocyte adhesion and transendothelial migration. This is mediated by the membrane-proximal Ig-like domain 2 of JAM-A; however, the location of the JAM-A binding site in LFA-1 has not been identified. We have deleted the I domain in the _L subunit of LFA-1 and expressed this _L mutant in _L-deficient Jurkat J-₂.7 cells to demonstrate that the I domain of LFA-1 is crucial for their adhesion to immobilized JAM-A. This was substantiated by blocking the stimulated adhesion of wild-type Jurkat T cells or monocytic Mono Mac 6 cells to JAM-A using the I domain-directed mAb TS1/22 or the small molecule antagonist BIRT 377, which stabilizes the low-affinity conformation of the I domain. The immobilized LFA-1 I domain locked in the open high-affinity conformation was sufficient to support binding of transfected Chinese hamster ovary cells expressing JAM-A. Solid-phase binding assays confirmed a direct interaction of recombinant JAM-A with the immobilized locked-open I domain. These data provide the first evidence that the I domain of LFA-1 contains a functional binding site for JAM-A.

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