Human immunoglobulin A receptor (FcalphaRI, CD89) function in transgenic mice requires both FcR gamma chain and CR3 (CD11b/CD18).
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, FcalphaRI (CD89), triggers various effector functions in vitro, but its in vivo role remains unclear. Here, a transgenic mouse model is described in which FcalphaRI is expressed under its own regulatory sequences. Receptor expression and regulation by cytokines was comparable to the human situation and hFcalphaRI can trigger phagocytosis and lysis of tumor cells. To analyze the contribution of the FcR gamma chain or the beta2 integrin CR3 (CD11b/CD18) in FcalphaRI biological function, FcalphaRI transgenic mice were crossed with either FcR gamma chain -/- or CR3 -/- mice. In contrast to in vitro data, FcR gamma chain was essential for surface expression of hFcalphaRI in vivo. Functional studies in hFcalphaRI/ gamma-/-mice were, therefore, limited. In vitro studies showed FcR gamma chain to be necessary for phagocytosis. Neither hFcalphaRI expression nor phagocytosis, triggered via hFcalphaRI, were influenced by CR3. Remarkably, the capacity to lyse tumor targets was ablated in hFcalphaRI transgenic/ CR3-/- mice, although binding of neutrophils to tumor cells was intact. This shows a previously unrecognized importance of CR3 for hFcalphaRI-mediated antibody-dependent cellular cytotoxicity (ADCC).
van Egmond
M
M
Department of Immunology and Medarex Europe, University Medical Center Utrecht, Utrecht, The Netherlands.
van Vuuren
A J
AJ
Morton
H C
HC
van Spriel
A B
AB
Shen
L
L
Hofhuis
F M
FM
Saito
T
T
Mayadas
T N
TN
Verbeek
J S
JS
van de Winkel
J G
JG
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D018845:CD11 Antigens / Q000235:genetics / Q000276:immunology*; D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010587:Phagocytosis; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*
D015703:Antigens, CD; D018845:CD11 Antigens; D018821:CD18 Antigens; D016207:Cytokines; C036832:Fc(alpha) receptor; D011961:Receptors, Fc; D017452:Receptors, IgG