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* Laboratory of B-cell Development Research Center and
Department of Medical and Surgical Neonatology, Children Hospital "Bambino Gesù," Rome, Italy;
Department of Pediatrics and Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy;
Medical Genetics Laboratory, S. Orsola-Malpighi University Hospital, Bologna, Italy; and
¶ Division of Allergy and Clinical Immunology, Department of Clinical Medicine, University of Rome "La Sapienza," Rome, Italy
The receptor TLR9, recognizing unmethylated bacterial DNA (CpG), is expressed by B cells and plays a role in the maintenance of serological memory. Little is known about the response of B cells stimulated with CpG alone, without additional cytokines. In this study, we show for the first time the phenotypic modification, changes in gene expression, and functional events downstream to TLR9 stimulation in human B cell subsets. In addition, we demonstrate that upon CpG stimulation, IgM memory B cells differentiate into plasma cells producing IgM Abs directed against the capsular polysaccharides of Streptococcus pneumoniae. This novel finding proves that IgM memory is the B cell compartment responsible for the defense against encapsulated bacteria. We also show that cord blood transitional B cells, corresponding to new bone marrow emigrants, respond to CpG. Upon TLR9 engagement, they de novo express AID and Blimp-1, genes necessary for hypersomatic mutation, class-switch recombination, and plasma cell differentiation and produce Abs with anti-pneumococcal specificity. Transitional B cells, isolated from cord blood, have not been exposed to pneumococcus in vivo. In addition, it is known that Ag binding through the BCR causes apoptotic cell death at this stage of development. Therefore, the ability of transitional B cells to sense bacterial DNA through TLR9 represents a tool to rapidly build up the repertoire of natural Abs necessary for our first-line defense at birth.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Federica Capolunghi, Laboratory of B-cell Development Research Center, Children Hospital "Bambino Gesù," Piazza S. Onofrio 4, 00165 Rome, Italy. E-mail address: federica.capolunghi{at}opbg.net
2 Abbreviations used in this paper: DC, dendritic cell; PnPS, pneumococcal polysaccharide; AID, activation-induced cytidine deaminase; Blimp, B lymphocyte-induced maturation protein.
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