Protecting positively selected B cell clones from apoptosis

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.

Published December 14, 2015, by The JCI

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MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosis
Rinako Nakagawa, … , Robert Brink, Elena Vigorito
Rinako Nakagawa, … , Robert Brink, Elena Vigorito
Published December 14, 2015
Citation Information: J Clin Invest. 2016;126(1):377-388. https://doi.org/10.1172/JCI82914.
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Research Article Immunology

MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosis

Abstract

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 Mir155 deletion impairs affinity maturation and promotes the premature collapse of GCs. We determined that miR-155 directly inhibits the Jumonji family member JARID2, which enhances B cell apoptosis when overexpressed, and thereby promotes GC B cell survival. Our findings also suggest that there is cooperation between c-MYC and miR-155 during the normal GC response, a cooperation that may explain how c-MYC and miR-155 can collaboratively function as oncogenes.

Authors

Rinako Nakagawa, Rebecca Leyland, Michael Meyer-Hermann, Dong Lu, Martin Turner, Giuseppina Arbore, Tri Giang Phan, Robert Brink, Elena Vigorito

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