title: IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression and activity.
abstract: The transcription factor interferon regulatory factor-4 (IRF4) is expressed in B cells at most developmental stages. In antigen-activated B cells, IRF4 controls germinal center formation, class-switch recombination, and the generation of plasma cells. Here we describe a novel function for IRF4 in the homeostasis of mature B cells. Inducible deletion of irf4 specifically in B cells in vivo led to the aberrant accumulation of irf4-deleted follicular B cells in the marginal zone (MZ) area. IRF4-deficient B cells showed elevated protein expression and activation of NOTCH2, a transmembrane receptor and transcriptional regulator known to be required for MZ B cell development. Administration of a NOTCH2-inhibitory antibody abolished nuclear translocation of NOTCH2 in B cells within 12 h and caused a rapid and progressive disintegration of the MZ that was virtually complete 48 h after injection. The disappearance of the MZ was accompanied by a transient increase of MZ-like B cells in the blood rather than increased B cell apoptosis, demonstrating that continued NOTCH2 activation is critical for the retention of B cells in the MZ. Our results suggest that IRF4 controls the positioning of mature B cells in the lymphoid microenvironments by regulating NOTCH2 expression. These findings may have implications for the understanding of B cell malignancies with dysregulated IRF4 and NOTCH2 activity.
authors: Herbert Irving Comprehensive Cancer Center, 2 Department of Pathology and Cell Biology, and 3 Department of Microbiology and Immunology, Columbia University, New York, NY 10032.
authors: Giorgia
authors: G
authors: Simonetti
authors: Amanda
authors: A
authors: Carette
authors: Kathryn
authors: K
authors: Silva
authors: Haowei
authors: H
authors: Wang
authors: Nilushi S
authors: NS
authors: De Silva
authors: Nicole
authors: N
authors: Heise
authors: Christian W
authors: CW
authors: Siebel
authors: Mark J
authors: MJ
authors: Shlomchik
authors: Ulf
authors: U
authors: Klein
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010641:Phenotype; D051883:Receptor, Notch2 / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D049452:Green Fluorescent Proteins; D050835:Interferon Regulatory Factors; D051883:Receptor, Notch2; D000099218:Interferon Regulatory Factor-4; C497765:Notch2 protein, mouse