Regulation of plasma cell differentiation, migration and class-switch by c-Myb and T-bet

Abstract

Abstract Humoral responses are tailored to respond most effectively to the invading pathogen. To achieve this, long lasting, protective antibodies of an affinity and isotype appropriate for the immunising antigen or infecting pathogen are produced mainly within germinal centres (GC). Here, we detail the critical, interdependent roles of the transcription factors c-Myb and T-bet in regulating GC egress and plasma cell differentiation. Deletion of c-Myb in mature B cells led to aberrant up-regulation of plasma cell transcription factors within the GC. Indeed, a subset of cycling cells within the GC secreted antibody and were CD138+ Blimp-1-GFP+. T-bet-regulated genes were also modulated, resulting in significantly elevated serum IgG2c and CXCR3 expression on plasma cells despite a Th2-biased immunization with NP-KLH in alum. These aberrant plasma cells within the GC were no longer evident upon deletion of T-bet in c-Myb-deficient mice. Surprisingly, this interplay between transcription factor networks also occurred during a response to influenza infection, in which T-bet expression is a normal component of B cell responses in wild-type mice. Chromatin accessibility studies of the T-bet promoter revealed that wild-type GC B cells from flu-infected mice had an increase in accessibility in comparison to naïve B cells, as expected. In line with the cellular data, however, there was an even further increase in chromatin accessibility in c-Myb-deficient GC B cells. Therefore, c-Myb establishes a transcription factor network during an immune response that can modulate the transcriptional network of T-bet and subsequent coordination of GC egress with plasma cell differentiation.