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(Journal of Leukocyte Biology. 2000;68:641-649.)
© 2000 by Society for Leukocyte Biology

_Mß₂ (CD11b/CD18, Mac-1) integrin activation by a unique monoclonal antibody to _M I domain that is divalent cation-sensitive

Randal P. Orchekowski^*, Janet Plescia, Dario C. Altieri and Mary Lynn Bajt^*

^* Cell and Molecular Biology, Pharmacia Corporation, Kalamazoo, Michigan; and
Department of Pathology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut

The ß₂ (CD18) leukocyte integrins play a key role in normal and inflammatory immune responses. In resting leukocytes, these receptors do not bind ligands. However, when leukocytes are exposed to an appropriate agonist, high-affinity ligand binding is achieved, presumably as a result of conformational changes in the integrin. In this study, we describe a novel monoclonal antibody, mAb 6C1, directed against the _M subunit, which directly induces adhesion of _Mß₂-transfected CHO cells to fibrinogen, ICAM-1, and iC3b. Induction of binding could also be accomplished by monovalent Fab fragments of mAb 6C1 at concentrations similar to that observed with intact IgG, demonstrating stimulation of adhesion was not because of receptor cross-linking at the cell surface. The binding of mAb 6C1 induces conformational changes in the receptor, as evidenced by the expression of an "activation reporter" epitope recognized by mAb 24. The binding of mAb 6C1 is modulated by divalent cations. Mn²⁺ promoted high levels of 6C1 binding, and Mg²⁺ supported low levels of binding, however Ca²⁺ failed to support binding. A unique distinction of mAb 6C1 is localization of its epitope to the _M I domain. The _M I domain is essential for ligand binding, can directly bind divalent cations, and participates in the regulation of _Mß₂ ligand-binding affinity. Thus, these studies have identified a novel _M I domain activation epitope of _Mß₂ and support the idea that the I domain modulates the activational state of the ß₂ integrins.

Key Words: adhesion • active conformation • inflammatory immune response

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