The affinity that B cells have for antigen is increased through an iterative process known as affinity maturation. This process involves the cycling of B cells cycle between somatic hypermutation and proliferation in the germinal center (GC) dark zone (DZ), allowing the acquisition of mutations that enhance antigen affinity, and clonal selection in the GC light zone (LZ). The oncogenic microRNA miR-155 is required for efficient affinity maturation and GC maintenance; however, the underlying molecular mechanisms are unclear. In this episode, Rinako Nakagawa and Elena Vigorito discuss their work, which reveals that miR-155 is highly expressed in positively selected c-MYC+ LZ B cells and inhibits JARID2 to prevent apoptosis of positively selected B cells. Together, the results of this study provide important insight in the GC response and how c-MYC and miR-155 may collaborate as oncogenes.
The production of high-affinity antibodies by B cells is essential for pathogen clearance. Antibody affinity for antigen is increased through the affinity maturation in germinal centers (GCs). This is an iterative process in which B cells cycle between proliferation coupled with the acquisition of mutations and antigen-based positive selection, resulting in retention of the highest-affinity B cell clones. The posttranscriptional regulator microRNA-155 (miR-155) is critical for efficient affinity maturation and the maintenance of the GCs; however, the cellular and molecular mechanism by which miR-155 regulates GC responses is not well understood. Here, we utilized a miR-155 reporter mouse strain and showed that miR-155 is coexpressed with the proto-oncogene encoding c-MYC in positively selected B cells. Functionally, miR-155 protected positively selected c-MYC+ B cells from apoptosis, allowing clonal expansion of this population, providing an explanation as to why
Rinako Nakagawa, Rebecca Leyland, Michael Meyer-Hermann, Dong Lu, Martin Turner, Giuseppina Arbore, Tri Giang Phan, Robert Brink, Elena Vigorito