APRIL signaling in human antibody secreting cells promotes cellular response via p38 and differential immediate early gene regulation

Abstract

Abstract Long-lived antibody secreting cells (ASCs) persist as quiescent plasma cells (PCs) in niche microenvironments. However, we know little about how ASCs integrate these signals to drive changes in function. APRIL is an important in vivo niche factor, for which the primary receptor is BCMA, but to our knowledge APRIL-induced signaling and consequent gene regulation in primary human ASCs are poorly defined. In particular, little is known of signals that APRIL generates at the transition from proliferative plasmablast to quiescent plasma cell, an important transition in ASC differentiation. Using a model system of in vitro PC differentiation, which utilizes APRIL signaling as a key survival promoting factor, we demonstrate that significant levels of multimerized mega-APRIL are needed to deliver signals into ASCs. This in part reflects a process of cell intrinsic shedding of BCMA, the APRIL receptor, as previously reported by others. Blockade of proteolytic shedding by gamma secretase inhibitors enhances surface BCMA expression and mega-APRIL induced PC survival, generating phenotypically mature PCs with prolonged longevity from in vitro and ex vivo plasmablasts. At the plasmablast to plasma cell transition APRIL induces a selective pattern of MAP kinase activation in human ASCs, preferentially activating p38. This contrasts to another niche signal, SDF1, which preferentially targets ERK. Differential gene regulatory responses are evident for immediate early genes, with APRIL producing a preferential activation of FOSB relative to FOS or EGR1. The results provide the basis for systematically exploring the signaling and gene regulatory networks involved in the response of human ASCs to niche factors supporting PC survival.