APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells.
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.
Belnoue
Elodie
E
World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
Pihlgren
Maria
M
McGaha
Tracy L
TL
Tougne
Chantal
C
Rochat
Anne-Françoise
AF
Bossen
Claudia
C
Schneider
Pascal
P
Huard
Bertrand
B
Lambert
Paul-Henri
PH
Siegrist
Claire-Anne
CA
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*
D053264:B-Cell Activating Factor; D011509:Proteoglycans; D012333:RNA, Messenger; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13