Human Immunoglobulin A Receptor (FcαRI, CD89) Function in Transgenic Mice Requires Both FcR γ Chain and CR3 (CD11b/CD18)

Abstract

AbstractEven though more immunoglobulin A (IgA) is produced in humans than all other isotypes combined, relatively little is known about receptors that bind the Fc part of IgA. The myeloid IgA receptor, FcαRI (CD89), triggers various effector functions in vitro, but its in vivo role remains unclear. Here, a transgenic mouse model is described in which FcαRI is expressed under its own regulatory sequences. Receptor expression and regulation by cytokines was comparable to the human situation and hFcαRI can trigger phagocytosis and lysis of tumor cells. To analyze the contribution of the FcR γ chain or the β2 integrin CR3 (CD11b/CD18) in FcαRI biological function, FcαRI transgenic mice were crossed with either FcR γ chain −/− or CR3 −/− mice. In contrast to in vitro data, FcR γ chain was essential for surface expression of hFcαRI in vivo. Functional studies in hFcαRI/ γ−/−mice were, therefore, limited. In vitro studies showed FcR γ chain to be necessary for phagocytosis. Neither hFcαRI expression nor phagocytosis, triggered via hFcαRI, were influenced by CR3. Remarkably, the capacity to lyse tumor targets was ablated in hFcαRI transgenic/ CR3−/− mice, although binding of neutrophils to tumor cells was intact. This shows a previously unrecognized importance of CR3 for hFcαRI-mediated antibody-dependent cellular cytotoxicity (ADCC).