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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2755-2764.
Prepublished online as a Blood First Edition Paper on January 7, 2008; DOI 10.1182/blood-2007-09-110858.
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Submitted September 6, 2007
Accepted December 27, 2007
APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early life bone marrow stromal cells
Elodie Belnoue, Maria Pihlgren, Tracy L McGaha, Chantal Tougne, Anne-Francoise Rochat, Claudia Bossen, Pascal Schneider, Bertrand Huard, Paul-Henri Lambert, and Claire-Anne Siegrist*
World Health Organization Collaborating Center for Vaccinology & Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland
Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
Louis Jeantet Laboratory, Departments of Dermatology and Pathology-Immunology, Univesity Medical Center and Hospital, Geneva, Switzerland
* Corresponding author; email: claire-anne.siegrist{at}medecine.unige.ch.
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 APRIL and BAFF/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/PC survival/differentiation, we show that APRIL induces the expression of Bcl-XL 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.
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