Human bone marrow plasma cell survival is independent of APRIL

Abstract

Abstract A fraction of the circulating antibody (Ab)-secreting cells (ASC) matures into long-lived plasma cells (LLPC) in the bone marrow (BM) microniches. Previous studies showed that ASC survival and longevity require APRIL, which upon binding its receptors, BCMA or TACI, activates PI3K/Akt (and its downstream mTOR) pathways and upregulates the expression of antiapoptotic proteins Mcl-1 and Bcl-2. Later work revealed that APRIL binding to SDC-1 (CD138), a cell-surface heparin sulfate proteoglycan (HSPG), also enables delivery of survival signals. Recently, we showed that APRIL is crucial in the ex vivo survival of early-minted human blood ASC. Here, using an in vitro cell-free BM microniche system, we demonstrate the differential roles of APRIL in the survival of human blood ASC and BM plasma cells (PC) and LLPC. APRIL substantially enhanced the survival of both CD138+ and CD138− ASC populations in the blood, which highly expressed BCMA. In contrast, it had no survival advantage on BM PC or LLPC, despite their high BCMA expression. Additionally, anti-CD138 Ab inhibited the survival of both blood ASC and BM PC and LLPC, including CD138− cell subsets, suggesting inhibiting the later CD138 upregulation also affects blood ASC survival. These data suggest that APRIL is important for the survival of early-minted blood ASC but not BM PC or LLPC. In conclusion, APRIL is an important survival and imprinting factor of blood ASC but is not required for LLPC maintenance.