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 1

miR-155 in B cells is required for the maintenance of the GC response.

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miR-155 in B cells is required for the maintenance of the GC response. S...
SWHEL Mir155+/+ or SWHEL Mir155–/– donor B cells were adoptively transferred into CD45.1+ congenic recipient mice that were then injected with HEL3X-SRBC. Spleen cells from these mice were analyzed by flow cytometry at the indicated days. (A)The gating strategy and experimental design are shown (left). The FACS plot analyzing SWHEL Mir155+/+ donor cell at day 4 is shown as an example. The number of donor-derived (CD45.1–CD45.2+) HEL-specific GC B cells was calculated based on the proportion of cells stained as CD38loCD95+ and HEL-binders and further divided as CXCR4hiCD86lo for DZ B cells and CXCR4loCD86hi for LZ B cells (right). Data represent 1 out of 3 independent experiments. The mean ± SEM is shown (SWHEL Mir155+/+; d4, n = 6; d5, n = 4; d6, n=5; and d7, n = 4. SWHEL Mir155–/–; d4, n = 6; d5, n = 4; d6, n = 8; and d7, n = 4). Two-tailed unpaired t test, SWHEL Mir155+/+ LZ vs. SWHEL Mir155–/– LZ, at d5, d6, and d7. *P < 0.05, **P < 0.005, ***P < 0.0005, and the same for SWHEL Mir155+/+ DZ vs. SWHEL Mir155–/– DZ. (B) Splenic sections containing adoptively transferred B cells of the indicated genotype were stained for IgD in red, CD3 in blue, and HEL binding in green at d3.5 or d5. Arrows indicate GCs. Scale bar: 50 μm.