Capolunghi Federica, Cascioli Simona, Giorda Ezio, Rosado Maria Manuela, Plebani Alessandro, Auriti Cinzia, Seganti Giulio, Zuntini Roberta, Ferrari Simona, Cagliuso Maria, Quinti Isabella, Carsetti Rita
Laboratory of B-cell Development Research Center, Department of Medical and Surgical Neonatology, Children Hospital Bambino Gesù, and Department of Clinical Medicine, University of Rome La Sapienza, Italy.
J Immunol. 2008 Jan 15;180(2):800-8. doi: 10.4049/jimmunol.180.2.800.
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.
识别未甲基化细菌DNA（CpG）的受体TLR9由B细胞表达，并在血清学记忆的维持中发挥作用。关于仅用CpG刺激B细胞（无其他细胞因子）的反应，目前了解甚少。在本研究中，我们首次展示了人B细胞亚群中TLR9刺激后的表型修饰、基因表达变化及下游功能事件。此外，我们证明在CpG刺激下，IgM记忆B细胞可分化为产生针对肺炎链球菌荚膜多糖的IgM抗体的浆细胞。这一新发现证明IgM记忆是负责抵御有荚膜细菌的B细胞区室。我们还表明，对应于新从骨髓迁出的脐血过渡性B细胞对CpG有反应。在TLR9激活后，它们从头表达AID和Blimp-1，这是高体细胞突变、类别转换重组及浆细胞分化所必需的基因，并产生具有抗肺炎球菌特异性的抗体。从脐血中分离出的过渡性B细胞在体内尚未接触过肺炎球菌。此外，已知在此发育阶段通过BCR结合抗原会导致细胞凋亡死亡。因此，过渡性B细胞通过TLR9感知细菌DNA的能力是一种快速建立出生时一线防御所需天然抗体库的工具。
