No significant increase in lymphocyte populations in the BALs from quintuple-KO mice could be observed, either by flow cytometry (BMMC supernatant, 0.10% 0.03%; IgE-ICs, 0.09% 0.06%; BMMC supernatant plus IgE-ICs, 0.17% 0.10%; variations not significant, Studentsttest) or by cytospin analysis (data not shown). human FceRI(), which is expressed by macrophages and neutrophils and especially in atopic individuals, rather than an equivalent of hFcRIIIA, which has no affinity for IgE. Using mice lacking 3 FcRs and 2 FceRs and expressing mFcRIV only, we further demonstrated that mFcRIV promotes IgE-induced lung inflammation. These data lead us to propose a mouse model of IgE-induced lung inflammation in which cooperation exists between mast cells and mFcRIV-expressing lung cells. We therefore suggest that a similar cooperation may occur between mast cells and hFceRI-expressing lung cells in human allergic asthma. == Introduction == A novel murine receptor for the Fc portion of mAbs (FcR) was recently cloned on the basis of a bioinformatics database search. This receptor is among the many FcR-like (FCRL) molecules identified in mammals, and it was first named murine FCRL3 (NCBI sequenceBC027310) (1). FCRLs have no known ligand except murine FCRL3. As it was found to bind IgG, mouse FCRL3 was renamed mFcRIV. mFcRIV binds mouse IgG2a and IgG2b with an intermediate affinity (equilibrium association constant [KA] 2.9 107M1and 1.7 107M1, respectively; ref.2). Two main types of FcRs can be distinguished on the basis of their affinity for immunoglobulins. Monomeric immunoglobulins can bind to high-affinity (KA 1081010M1) but not to low-affinity (KA 106M1) receptors. As a consequence, a proportion of high-affinity receptors are occupied in vivo, whereas low-affinity receptors remain free, even though they are exposed to high concentrations of circulating immunoglobulins in vivo (3). Immune complexes (ICs) bind to low-affinity receptors with a high avidity. They also bind to high-affinity receptors. Both types of receptors signal when they are aggregated at the cell surface by mAbs and multivalent antigen (Ag). Rather than on the affinity of receptors, signals generated upon FcR aggregation depend on functional motifs contained in the intracellular domains of FcR subunits engaged in receptor aggregates. mFcRIV is an activating receptor (2). Like most activating FcRs, it associates with the common FcR subunit. FcR is a homodimer that contains 2 immunoreceptor tyrosine-based activation motifs (ITAM). The phosphorylation of FcR ITAMs by Src kinases initiates the constitution of an TC-A-2317 HCl intracellular signaling complex, which activates an array of metabolic pathways leading to cell responses. FcR-dependent activation signals are amplified by FcR (4), another ITAM-containing subunit expressed in TC-A-2317 HCl mast cells and basophils. mFcRIV does not associate with FcR. In order for mFcRIV to be expressed at the cell membrane, it must associate with FcR (2). FcR indeed determines the membrane expression of multichain FcRs, i.e., mFcRIV, human and murine high-affinity receptors for IgE (FcRI) and IgG (FcRI), and human and murine low-affinity receptors for IgG (FcRIIIA) (5). FcR associates with multichain FcRs (6) expressed in mast cells and basophils (7). It is, however, mandatory for the expression of mFcRI only (8,9). hFcRI can therefore be expressed with FcR [hFcRI()] in mast cells and basophils or without in monocytes, macrophages, and neutrophils [hFcRI()], especially in atopic individuals. hFcRI may therefore be expressed Gata3 in 2 forms depending on the cell type and on the species. mFcRIV is expressed in mouse monocytes, macrophages, and neutrophils. mFcRIV was recently reported to bind mouse IgE of the b (IgEb) but not of the a (IgEa) allotype (10). We show here that mFcRIV is a low-affinity receptor for IgE irrespective of the 2 2 known allotypes (11,12). FcRIV does not exist in humans. On the basis of sequence homology in extracellular domains, hFcRIIIA was proposed to be the TC-A-2317 HCl human homolog of mFcRIV (1). We show that hFcRIIIA has no detectable affinity for human IgE. We also show that, in spite of having an intermediate affinity, mFcRIV binds mouse IgG2a and IgG2b as monomers and functions as a high-affinity receptor. IgE ICs can, however, displace IgG2 from mFcRIV. When aggregated by IgE ICs of both allotypes, mFcRIV triggered Ca2+responses in transfected cells and induced macrophage-like transformed cells and peritoneal macrophages to secrete TNF-. hFcRI().