TLR ligation triggers somatic hypermutation in transitional B cells inducing the generation of IgM memory B cells

A Aranburu, S Ceccarelli, E Giorda… - The Journal of …, 2010 - journals.aai.org
A Aranburu, S Ceccarelli, E Giorda, R Lasorella, G Ballatore, R Carsetti
The Journal of Immunology, 2010journals.aai.org
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 …
Abstract
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.
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