Mac-1 promotes FcγRIIA-dependent cell spreading and migration on immune complexes

The integrin Mac-1 plays a critical role in Fc receptor (FcR)- mediated antibody-dependent cellular cytotoxicity (ADCC). However, the mechanism by which Mac-1 facilitates the functions of Fc gamma RIIA, a major FcR expressed on human leukocytes, is not fully understood. We report here that Mac-1 sustains cell adhesion, enhances cell spreading, and accelerates cell migration on preformed immune complexes (ICs) by directly interacting with Fc gamma RIIA but not with the IC substrate. Coupling Mac-1 to Fc gamma RIIA allows Fc gamma RIIA to reside in the leading front of actin polymerization at the filopodial extension and thus could potentially enhance Fc gamma RIIA-mediated cell spreading and migration. The direct interaction between Mac-1 and Fc gamma RIIA is demonstrated by co-immunoprecipitation, by cell surface co-localization, and by solid-phase binding assays using recombinant alpha I-M-domain and soluble Fc gamma RIIA. Further mutational analysis identifies the E-253-R-261 sequence within the alpha I-M-domain as part of the Fc gamma RIIA binding interface within Mac-1. Altogether, these results demonstrate that Fc gamma RIIA recognizes Mac-1 via the alpha I-M-domain but not the lectin domain, a distinct feature from other FcRs, and that Mac-1 binding confers Fc gamma RIIA with the ability to prolong cell adhesion as well as to spread and migrate on the ICs, leading to effective cell killing by ADCC.