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

Abstract

Even 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, FcRI (CD89), triggers various effector functions in vitro, but its in vivo role remains unclear. Here, a transgenic mouse model is described in which FcRI is expressed under its own regulatory sequences. Receptor expression and regulation by cytokines was comparable to the human situation and hFcRI 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 FcRI biological function, FcRI 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 hFcRI in vivo. Functional studies in hFcRI/ γ−/−mice were, therefore, limited. In vitro studies showed FcR γ chain to be necessary for phagocytosis. Neither hFcRI expression nor phagocytosis, triggered via hFcRI, were influenced by CR3. Remarkably, the capacity to lyse tumor targets was ablated in hFcRI transgenic/ CR3−/− mice, although binding of neutrophils to tumor cells was intact. This shows a previously unrecognized importance of CR3 for hFcRI-mediated antibody-dependent cellular cytotoxicity (ADCC).

The Fc receptor γ‐chain is necessary and sufficient to initiate signalling through glycoprotein VI in transfected cells by the snake C‐type lectin, convulxin

“…Arrows indicate the position of GPVI and the FcR c-chain. n ¼ 3. expression of FcaR and FccRI [18,19] possibly through prevention of their degradation [20]. Consistent with this, mice depleted of the FcR c-chain did not express detectable GPVI [21], raising the possibility that in vivo, unlike in cell lines, GPVI may be degraded in the absence of the FcR c-chain.…”

Immunoglobulin A: magic bullet or Trojan horse?

“…In vivo studies on IgA antitumour therapy are limited, partially because mice do not express FcaRI. In a FcaRI transgenic mouse model [53], IgA2 anti-EGFR antibodies induced tumour cell killing, which was likely mediated by macrophages [54]. More studies are necessary to determine the contribution of neutrophils after FcaRI targeting in vivo.…”

Targeting Antigens to Dendritic Cell Receptors for Vaccine Development

“…Fc lphaRI is expressed on myeloid cells, interstitial-type DCs, CD34+ DCs, and monocyte derived DCs [208]. Fc lphaR1 binds to Porphyromonas gingivalis, Bordetella pertussis, and Candida albicans stimulating efficient immune responses for their elimination [209][210][211][212][213]. Cross-linking of Fc lphaRI induced internalization of receptor and activation of DCs; however, there was very minimal antigen presentation [214,215].…”