title: APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells.
abstract: The persistence of serum IgG antibodies elicited in human infants is much shorter than when such responses are elicited later in life. The reasons for this rapid waning of antigen-specific antibodies elicited in infancy are yet unknown. We have recently shown that adoptively transferred tetanus toxoid (TT)-specific plasmablasts (PBs) efficiently reach the bone marrow (BM) of infant mice. However, TT-specific PBs fail to persist in the early-life BM, suggesting that they fail to receive the molecular signals that support their survival/differentiation. Using a proliferation-inducing ligand (APRIL)- and B-cell activating factor (BAFF) B-lymphocyte stimulator (BLyS)-deficient mice, we demonstrate here that APRIL is a critical factor for the establishment of the adult BM reservoir of anti-TT IgG-secreting cells. Through in vitro analyses of PB/plasma cell (PC) survival/differentiation, we show that APRIL induces the expression of Bcl-X(L) by a preferential binding to heparan sulfate proteoglycans at the surface of CD138(+) cells. Last, we identify BM-resident macrophages as the main cells that provide survival signals to PBs and show that this function is slowly acquired in early life, in parallel to a progressive acquisition of APRIL expression. Altogether, this identifies APRIL as a critical signal for PB survival that is poorly expressed in the early-life BM compartment.
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
authors.forename: Elodie
authors.initials: E
authors.lastname: Belnoue
authors.forename: Maria
authors.initials: M
authors.lastname: Pihlgren
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
authors.forename: Chantal
authors.initials: C
authors.lastname: Tougne
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Rochat
authors.forename: Claudia
authors.initials: C
authors.lastname: Bossen
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Bertrand
authors.initials: B
authors.lastname: Huard
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Lambert
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000276:immunology*; D002460:Cell Line; D002470:Cell Survival; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology*; D011485:Protein Binding; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology* / Q000276:immunology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000276:immunology*
chemical_list: D053264:B-Cell Activating Factor; D011509:Proteoglycans; D012333:RNA, Messenger; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13