title: 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.forename: Rinako
authors.initials: R
authors.lastname: Nakagawa
authors.forename: Rebecca
authors.initials: R
authors.lastname: Leyland
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer-Hermann
authors.forename: Dong
authors.initials: D
authors.lastname: Lu
authors.forename: Martin
authors.initials: M
authors.lastname: Turner
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Arbore
authors.forename: Tri Giang
authors.initials: TG
authors.lastname: Phan
authors.forename: Robert
authors.initials: R
authors.lastname: Brink
authors.forename: Elena
authors.initials: E
authors.lastname: Vigorito
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology*; D002470:Cell Survival; D018858:Germinal Center / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis*
chemical_list: C093650:Jarid2 protein, mouse; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016271:Proto-Oncogene Proteins c-myc; D063151:Polycomb Repressive Complex 2