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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Figure 6

GC phenotype due to miR-155 deficiency in B cells in silico.

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GC phenotype due to miR-155 deficiency in B cells in silico. (A–D) Simul...
(A–D) Simulations of WT GC immunized with HEL3x (black lines and black-filled bars) or HEL (gray dashed lines) were used for validation of the reference simulations with in vivo experimental data (black open diamonds [A and B] and black open bars [C and D] for HEL3x, and gray open squares [A and B] for HEL). In silico miR-155 KO experiments were performed and compared with in vivo experimental results (red open circles [A and B] and red open bar [C and D]) assuming various effects of miR-155 KO: reduced cell cycle speed (magenta lines [A and B] and magenta-filled bar [C and D]), reduced number of divisions during GC expansion (light-green lines [A and B] and light-green–filled bar [C and D]), and in addition, during GC selection phase (orange lines [A and B] and orange-filled bar [C and D]), defect of BCR leading to reduced antigen collection (blue lines [A and B] and blue-filled bar [C and D]), defect in antigen processing or presentation on peptide-MHC (cyan lines [A and B] and cyan-filled bar [C and D]), or increased apoptosis rate in the B cell subset positively selected by follicular T helper cells (green lines [A and B] and green-filled bar [C and D]). The GC phenotype is characterized by the total GC size (A), the number of output cells generated by one GC in the last hour (B), the fraction of high-affinity GC B cells at day 7 after immunization (C), and the fraction of apoptotic GC B cells at day 5 after immunization (D). All lines and bars are the mean of 50 simulations. Standard deviations for A and B and time courses for C and D are provided in Supplemental Figure 4.