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 4

miR-155 is coexpressed with c-MYC in a subset of LZ B cells.

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miR-155 is coexpressed with c-MYC in a subset of LZ B cells. Splenic B c...
Splenic B cells derived from Mycgfp/gfp SWHEL Mir155+/+ or Mycgfp/gfp SWHEL Mir155–/– mice were adoptively transferred into CD45.1+ congenic recipients, which were injected with HEL3X-SRBC. (A) Four days later, CD45.1–CD45.2+CD38loCD95+ HEL–specific donor-derived splenic GC B cells were gated as DZ or LZ and further divided based on GFP expression. The mean ± SEM from 2 independent sorting experiments is shown (n = 6). (B) Four days after adoptive transfer of Mycgfp/gfp SWHEL Mir155+/+ cells, DZ GFP–, DZ GFP+, LZ GFP–, and LZ GFP+ cells were single cell sorted according to the gates shown in A from 3 mice, and miR-155 expression was measured by qPCR using U6 for normalization (DZ GFP–, n = 58; DZ GFP+, n = 50; LZ GFP–, n = 57; LZ GFP+, n = 46). Histograms show the distribution of cells on the basis of miR-155 expression in log-transformed arbitrary units. Bars are nudged to prevent overlapping. Background level was established by assessing the expression of miR-155 in Mir155–/– GC B cells.