Pre-existing CD19-independent GL7− Breg cells are expanded during inflammation and in mice with lupus-like disease

• GL7− B cell pool in lupus-like mice contained substantially more Bregs.
• Differentiation of GL7− B cells into Breg cells does not require CD19 or Bcl6.
• Pre-existing GL7−IL-10+ Breg cells are expanded during inflammation.
• GL7− Breg cells in the spleen suppressed inflammatory responses in lupus-like mice.

Interleukin 10 (IL-10)-producing regulatory B-cells (Bregs) suppress inflammatory responses that mediate autoimmune diseases. However, it is unknown whether Bregs derive from a pre-existing dedicated B-cell lineage or if any B-cell can differentiate into Bregs in response to BCR or TLR activation. GL7+ B-cells are antigen-experienced differentiated B-cells while GL7−/lo are at an early stage of B-cell differentiation. While both GL7−/lo and GL7+ B cells can produce IL-10, differentiation of GL7− B-cells into Bregs does not require CD19- or Bcl6-induced signals, suggesting that BCR-induced proliferation or Ig class-switching is not necessary for generation of Breg cells. Of particular importance, we show that GL7− Breg cells are dramatically expanded in lupus-like mice and GL7− Bregs suppressed inflammatory responses in lupus-like mice by inducing expansion of Foxp3+Treg cells. Taken together, these results suggest that pre-existing GL7−IL-10+ cells are expanded during inflammation, differentiate into GL7+ Bregs and contribute to immune-regulation in lupus-like mice.