Blimp1 controls GC B cell expansion and exit through regulating cell cycle progression and key transcription factors BCL6 and IRF4

Abstract

Abstract Blimp1 is required for plasma cell differentiation and antibody production. Blimp1 is also expressed in some dark zone germinal center (GC) B cells (GCBC), however, the exact role of Blimp1 in regulating GC B cell function is not clear. To investigate this, we generated chimeric mice using equal mixtures of bone marrow (BM) from Blimp1+/+ CD19Cre and Blimp1fl/fl CD19Cre mice. In these BM chimeras, Blimp1 sufficient and deficient B cells compete in the same environment, allowing us to examine the cell-intrinsic function of Blimp1 in GCBC, independent of environmental factors such as antibody or antigen levels. We discovered striking B cell-intrinsic roles for Blimp1. Blimp1 deficient B cells quickly dominate GCs and persist for a much longer time compared to the wild type cells. Mechanistically, Blimp1 deficiency increases the percentage of GCBC in the S phase. This difference seems independent of positive selection signals, because Blimp1 deficient GCBC express normal levels of c-Myc, a marker of positive selection. Importantly, Blimp1 deficient GCBC fail to downregulate BCL6 and upregulate IRF4, suggesting that Blimp1 induction in GCBC controls the expression of these key transcription factors, which are required for exit from the GC program. Consistent with this, memory B cells derived from the Blimp1 deficient B cells were only slightly increased, despite the fact that Blimp1 deficient GCBC are highly expanded and persistent. In addition, Blimp1 deficiency also reduced class-switching to IgG1 in response to NP-CGG immunization. These findings revealed unique antibody- and antigen-independent functions of Blimp1 in regulating GCBC responses that impact long-lived immune compartments.