title: The BCL6 RD2 domain governs commitment of activated B cells to form germinal centers.
abstract: To understand how the Bcl6 transcriptional repressor functions in the immune system, we disrupted its RD2 repression domain in mice. Bcl6RD2(MUT) mice exhibit a complete loss of germinal center (GC) formation but retain normal extrafollicular responses. Bcl6RD2(MUT) antigen-engaged B cells migrate to the interfollicular zone and interact with cognate T helper cells. However, these cells fail to complete early GC-commitment differentiation and coalesce as nascent GC aggregates. Bcl6 directly binds and represses trafficking receptors S1pr1 and Gpr183 by recruiting Hdac2 through the RD2 domain. Deregulation of these genes impairs B cell migration and may contribute to GC failure in Bcl6RD2(MUT) mice. The development of functional GC-TFH cells was partially impaired in Bcl6RD2(MUT) mice. In contrast to Bcl6(-/-) mice, Bcl6RD2(MUT) animals experience no inflammatory disease or macrophage deregulation. These results reveal an essential role for RD2 repression in early GC commitment and striking biochemical specificity in Bcl6 control of humoral and innate immune-cell phenotypes.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Laboratory Medicine and Immunobiology, Yale University, New Haven, CT 06520, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Gonzalez
authors.affiliation: Department of Laboratory Medicine and Immunobiology, Yale University, New Haven, CT 06520, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Cote
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Teater
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Kezhi
authors.initials: K
authors.lastname: Dai
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.affiliation: Department of Laboratory Medicine and Immunobiology, Yale University, New Haven, CT 06520, USA. Electronic address: ann.haberman@yale.edu.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Haberman
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: amm2014@med.cornell.edu.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D002465:Cell Movement; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology; D056464:Histone Deacetylase 2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051560:Proto-Oncogene Proteins c-bcl-6; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
chemical_list: C490010:Bcl6 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; C543809:Gpr183 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2