IgA Fc receptor I signals apoptosis through the FcRγ ITAM and affects tumor growth

Abstract

IntroductionThe receptor specific for the IgA Fc region (Fc␣RI or CD89) is expressed on blood myeloid cells, including monocyte/macrophages, dendritic cells, Kupffer cells, neutrophils, and eosinophils. 1 It transmits IgA-mediated effector functions via an IgA-binding module (K a about 10 6 M Ϫ1 ) that can be expressed with or without physical association with the disulfide-linked signaling adaptor FcR␥. 2,3 The FcR␥-associated receptor has signaling functions that involve an immunoreceptor tyrosine-based activation motif (ITAM), consisting of a conserved sequence that is present in the cytoplasmic domain of FcR␥ and is shared by different signaling subunits associated with receptors such as TCR and BCR and other FcRs. Although the ITAM was initially reported to mediate activating responses, recent data suggest that, in certain conditions, this motif can also trigger inhibitory responses mediated by a variety of receptors. [4][5][6] The latter include Fc␣RI, a dual-function receptor that can mediate both activating and inhibitory responses depending on the type of interaction with its ligand. Sustained multimeric aggregation mediates activation of target-cell functions, such as superoxide production, cytokine release, and antigen presentation. 7-9 Monomeric targeting with IgA or with a variety of anti-Fc␣RI (A77, A59, or A62, but not A3) Fab fragments triggers an inhibitory response to heterologous immunoreceptors such as Fc⑀RI and Fc␥R. 5 Like the activating functions, the inhibitory cross-talk is dependent on the FcR␥ ITAM. However, in contrast to receptors bearing an immunoreceptor tyrosine-based inhibitory motif (ITIM), such as FcR␥IIB, 10 the inhibitory signal does not require coaggregation. Monomeric targeting of Fc␣RI also has powerful anti-inflammatory activity in vivo because administration of anti-Fc␣RI Fab suppresses manifestations of allergic asthma in Fc␣RI transgenic mice. 5 Activation of certain FcRs also promotes cell death. Thus, Fc␥RIIB expressed on B cells not only terminates the activation signals of coengaged receptors, via an ITIM-dependent mechanism, but, in case of isolated aggregation, is also able to trigger an apoptotic response. 11 The latter involves ITIM and Src homology 2 domain-containing inositide phosphatase (SHIP)-independent and c-abl-family kinase-dependent pathways. [12][13][14] Recruitment of the Src homology 2 domain-containing phosphatase (SHP)-1 to the B-and T-cell antigen receptors (BCR and TCR) was also shown to negatively correlate with the induction of apoptosis. 12,15 Indeed, SHP-1-deficient mice are unusually susceptible to clonal deletion of their B-and T-cell compartment. [15][16][17] Although the precise mechanisms whereby SHP-1 negatively regulates apoptosis remains unknown, a possible hypothesis is that SHP-1 raises the threshold required for antigen receptor signaling spread thereby linking it to other biologic outcomes such as cell death.Incubation of neutrophils with immobilized IgA or secretory IgA also induces apopotosis. 18 This likely involves Fc␣RI, t...

Human IgA Fc Receptor FcαRI (CD89) Triggers Different Forms of Neutrophil Death Depending on the Inflammatory Microenvironment

“…Previous work showed that monovalent targeting by anti-FcaRI Fab resulted in monocyte apoptosis (47) and prevented or suppressed inflammation in transgenic animal models of renal inflammation (36) and allergic asthma (19). In line with these observations, our study points to an immunoregulatory role for FcaRI, although monovalent targeting of neutrophils by anti-FcaRI Fab had no effect on their viability, and death induction required natural IgA or divalent F(ab9) 2 or whole anti-FcaRI Ab in these cells.…”

Fcα receptor I activation induces leukocyte recruitment and promotes aggravation of glomerulonephritis through the FcRγ adaptor

“…IgA binding to FcaRI in the absence of sustained aggregation inhibits cellular responses initiated by a heterologous receptor and mediates apoptosis, while sustained clustering of FcaRI by IgA-IC leads to cell activation [11,12]. The multiple functions of FcaRI provide a molecular basis for the opposite roles of IgA as both an anti-and proinflammatory isotype [32].…”

“…Only the latter complex shows signal competence, as it bears an ITAM in the FcRc intracellular tail. It mediates either inflammatory or anti-inflammatory signaling, depending on multivalent or monovalent receptor targeting [11,12]. While monomeric IgA induces inhibition of heterologous receptors and apoptosis [11], multivalent aggregation of FcaRI by IC triggers several activating functions, including phagocytosis, superoxide production, and inflammatory cytokine secretion such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) [10].…”

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

“…Myeloid cell-expressed Fc␣RI and its associated ITAM-bearing FcR␥ subunit have recently emerged as new actors in immune homeostasis (19,20,40). They act as a dual-function module that can either activate cells or attenuate cell activation through heterologous ITAM-bearing receptors, depending on the interaction with its ligand.…”