Fas Apoptosis Inhibitory Molecule Enhances CD40 Signaling in B Cells and Augments the Plasma Cell Compartment

Abstract

Fas apoptosis inhibitory molecule (FAIM) was cloned as a mediator of Fas resistance that is highly evolutionarily conserved but contains no known effector motifs. In this study, we report entirely new functions of FAIM that regulate B cell signaling and differentiation. FAIM acts to specifically enhance CD40 signaling for NF-κB activation, IRF-4 expression, and BCL-6 down-regulation in vitro, but has no effect on its own or in conjunction with LPS or anti-Ig stimulation. In keeping with its effects on IRF-4 and BCL-6, FAIM overexpression augments the plasma cell compartment in vivo. These results indicate that FAIM is a new player on the field of B cell differentiation and acts as a force multiplier for a series of events that begins with CD40 engagement and ends with plasma cell differentiation.

A Novel Mechanism of B Cell–Mediated Immune Suppression through CD73 Expression and Adenosine Production

“…Cell surface phenotype was analyzed as previously described (57). In brief, cells pre-treated with 2.4G2 (5 μg/ml) were incubated with fluorescence-conjugated monoclonal antibodies in staining buffer (PBS containing 2% FCS and 0.05% NaN 3 ) on ice for 30 min and then washed with staining buffer.…”

Fas Apoptosis Inhibitory Molecule Expression in B Cells Is Regulated through IRF4 in a Feed-Forward Mechanism

“…FAIM affects B cells in two important ways: (1) FAIM opposes Fas-mediated apoptosis in B cells, an activity emphasized by the reported Fas sensitivity of FAIM-null immune cells, which in turn demonstrates the nonredundant nature of FAIM function; and (2) FAIM enhances CD40 signaling in B cells, augmenting NF-κB activation, BCL-6 loss, and IRF4 expression, as well as boosting the plasma cell population (1, 6, 7). These immune system effects, along with reported activities in neuronal cells and other cell types, have heightened interest in elucidating how FAIM expression is regulated in vivo.…”

“…Beyond apoptosis, FAIM influences signaling produced by nerve growth factor/TNF family members in B cells and in neuronal cells. Thus, we showed that B cell signaling resulting from CD40 triggering, but not from other stimuli, is increased by FAIM with respect to NF-κB activation, B cell lymphoma-6 (BCL-6) loss, and IFN regulatory factor (IRF)4 expression (7). Furthermore, in keeping with these effects, FAIM expression produces increased plasma cell differentiation in vivo (7).…”

“…Thus, we showed that B cell signaling resulting from CD40 triggering, but not from other stimuli, is increased by FAIM with respect to NF-κB activation, B cell lymphoma-6 (BCL-6) loss, and IFN regulatory factor (IRF)4 expression (7). Furthermore, in keeping with these effects, FAIM expression produces increased plasma cell differentiation in vivo (7). Comella and colleagues showed that FAIM increases (and knockdown of FAIM decreases) PC-12 cell signaling resulting from nerve growth factor receptor triggering in terms of NF-κB activation and neurite outgrowth (8).…”

The Power of Monoclonal Antibodies as Agents of Discovery: CD40 Revealed as a B Lymphocyte Costimulator

“…Cooperation with the BCR emerged as key to maximizing the effectiveness of the CD40 activation signal (9), whereas interaction with cytokine signals is important to the impact of CD40 on promoting Ig isotype switching (8,10) and also contributes to CD40-mediated enhancement of B cell proliferation (11,12). CD40 also cooperates with various additional immune-regulating receptors, including class II MHC (13), TLRs 7 and 9 (14-16), Fas apoptosis inhibitory molecule (17), and Notch (18).…”