The BCL6 RD2 Domain Governs Commitment of Activated B Cells to Form Germinal Centers

Summary To understand how the Bcl6 transcriptional repressor functions in the immune system, we disrupted its RD2 repression domain in mice. Bcl6 RD2 MUT mice exhibit a complete loss of germinal center (GC) formation but retain normal extrafollicular responses. Bcl6 RD2 MUT antigen-engaged B cells migrate to the interfollicular zone and interact with cognate T helper cells. However, these cells fail to complete early GC-commitment differentiation and coalesce as nascent GC aggregates. Bcl6 directly binds and represses trafficking receptors S1pr1 and Gpr183 by recruiting Hdac2 through the RD2 domain. Deregulation of these genes impairs B cell migration and may contribute to GC failure in Bcl6 RD2 MUT mice. The development of functional GC-T FH cells was partially impaired in Bcl6 RD2 MUT mice. In contrast to Bcl6 −/− mice, Bcl6 RD2 MUT animals experience no inflammatory disease or macrophage deregulation. These results reveal an essential role for RD2 repression in early GC commitment and striking biochemical specificity in Bcl6 control of humoral and innate immune-cell phenotypes.