TLR Ligation Triggers Somatic Hypermutation in Transitional B Cells Inducing the Generation of IgM Memory B Cells

被引:60
作者
Aranburu, Alaitz [1 ]
Ceccarelli, Sara [1 ]
Giorda, Ezio [1 ]
Lasorella, Rosa [2 ]
Ballatore, Giovanna [2 ]
Carsetti, Rita [1 ]
机构
[1] Bambino Gesu Pediat Hosp, Res Ctr, I-00165 Rome, Italy
[2] Osped St Eugenio, I-00144 Rome, Italy
关键词
DETERMINING REGION 3; DNA-POLYMERASE ETA; IMMUNOGLOBULIN GENES; DIVERSIFICATION; REPERTOIRE; MECHANISMS; AID; SPECIFICITY; EXPRESSION; ANTIBODIES;
D O I
10.4049/jimmunol.1002722
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
TLR9 activation by unmethylated CpG provides a homeostatic mechanism to maintain B cell memory in the absence of Ag. In this study, we demonstrate that CpG also triggers the generation of somatically mutated memory B cells from immature transitional B cells. In response to CpG, a fraction of transitional B cells proliferates and introduces somatic hypermutations in the H chain V regions. The nonproliferating pool of transitional B cells mostly maintains germline configurations. Mutations are VH specific: VH5 is the least mutated family, whereas VH1 and VH4/6 are the most mutated families. CpG stimulation also results in upregulation of VH5 transcripts in proliferating cells. Therefore, early recognition of bacterial DNA preferentially expands VH5-expressing B cells while inducing somatic hypermutations in other families. The mutation frequency, range, and type of substitutions observed in vitro are comparable to those found in memory B cells from the peripheral blood of Hyper IgM type 1 patients and the spleen of normal infants. The process triggered by TLRs may represent a first step leading to additional diversification of the germline repertoire and to the generation of memory B cells that will further refine their repertoire and specificity in the germinal centers. The Journal of Immunology, 2010, 185: 7293-7301.
引用
收藏
页码:7293 / 7301
页数:9
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