CD11c+ T-bet+ IgM memory B cells provide multi-lineage reconstitution of effector and memory B cells following challenge infection

Abstract

Abstract IgM memory B cells are now recognized as an important component of immunological memory. These cells have been proposed to act as a reservoir of broadly-reactive B cells that differentiate, in germinal centers, into high affinity class-switched effector B cells following antigen encounter. However, we propose IgM memory cells can differentiate into more than just germinal center and class-switched cells. To address this, we monitored the secondary response of CD11c+ T-bet+ IgM memory cells generated by Ehrlichia muris infection, by monitoring eYFP-labeled, flow cytometrically-purified, IgM memory cells following their transfer to naïve recipient mice and subsequent challenge infection. The IgM memory B cells differentiated into IgM-producing plasmablasts early following infection; this resulted in a 4-fold increase in IgM production, relative to control mice that did not receive memory cells. Other donor memory B cells entered germinal centers, down-regulated CD11c, and underwent class switching, generating switched memory B cells. Finally, some donor B cells were maintained as IgM memory cells. Upon secondary transfer and challenge, purified IgM memory cells underwent the same pattern of self-renewal and differentiation. Additionally, when IgM memory cell recipient mice were challenged with a virulent Ehrlichia strain, a reduction in bacterial burden was observed, indicating that IgM memory cells can provide immunity to challenge infection. Our findings also suggest that T-bet+ IgM memory cells act as a self-renewing population capable of repopulating the entire spectrum of effector and memory B cells during secondary infection, and demonstrate an important role for IgM memory cells in maintaining long-term immunity.