CpG Drives Human Transitional B Cells to Terminal Differentiation and Production of Natural Antibodies

Abstract

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.

Background paper to the updated pneumococcal vaccination recommendation for older adults in Germany

“…However, various studies have shown that PPS induce efficient activation of IgM + memory B cells (IgM + IgD + CD27 + ) and generation of long-lived plasma cells (CD38 + CD20 low ). This is accompanied by the generation and persistence of IgM and IgG antibodies against PPS [101][102][103][104][105][106][107][108]. IgM + memory B cells circulating in the blood are the peripheral correlates of the marginal zone B cells of the spleen.…”

Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children

“…The mechanisms underlying this condition are poorly known. In this context, of particular interest is the observation that transitional B cells stimulated by CpG terminally differentiate into plasma cells producing natural antibodies with innate pneumoccoccal specificity (42). It has been recently shown that TLR9 responsiveness to CpG stimulation is diminished in HIV-1 disease (43).…”

Mouse marginal zone B cells harbor specificities similar to human broadly neutralizing HIV antibodies

“…Compared with naïve or FO B cells, MZ B cells exhibit increased expression of costimulatory receptors, including complement receptor 2 and additional Toll-like receptors (TLRs) (48)(49)(50)(51). Human MZ B cells respond more robustly to Tcell-like help or TLR stimulation in vitro (52)(53)(54)(55). Rodent MZ B cells express CD1d, and human MZ B cells express CD1c (19), allowing these cells to provide cognate help to a wider range of T cells compared with FO B cells.…”