TLR9 drives the development of transitional B cells towards the marginal zone pathway and promotes autoimmunity

Maturation of B cells depends on environmental stimuli. Peripheral immature B cells develop into follicular pathway when antigenic stimulation is combined with T cell signals. Here, we wished to identify stimuli contributing to the development into marginal zone B cells known to be involved in autoimmune response. We found that TLR9 stimulation of transitional B cells induces proliferation and specific maturation into CD24− CD38+ CD21high CD23low IgMhigh IgDlow and Notch2high B cells characteristics of marginal zone B cells. Terminal differentiation into antibody-secreting cell associated with isotype switch commitment is also triggered which leads to a striking production of autoantibodies. Interestingly, mature B cells do not differentiate into marginal zone pathway following TLR9 stimulation, nor do transitional B cells under antigenic and T cell combined signals. These results suggest that transitional B cells are specifically sensitive to TLR9 stimulation to produce autoreactive marginal zone B cells.

► Transitional and mature B cells proliferate in response to TLR9 stimulation.
► TLR9 specifically differentiate transitional B cells into MZ B cells.
► TLR9-stimulated transitional B cells produce autoreactive antibodies.