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MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosis.
Nakagawa, Rinako Leyland, Rebecca Müller, A Lu, Dong Turner, Martin Arbore, Giuseppina Phan, Tri Giang Brink, Robert Vigorito, Elena
Nakagawa, Rinako
Leyland, Rebecca
Müller, A
Lu, Dong
Turner, Martin
Arbore, Giuseppina
Phan, Tri Giang
Brink, Robert
Vigorito, Elena
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2016-01-04
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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.
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MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosis. 2016, 126 (1):377-88 J. Clin. Invest.
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en
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1558-8238