title: Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism.
abstract: In response to antigenic stimulation, mature B cells interact with follicular helper T cells in specialized structures called germinal centers (GCs), which leads to the development of memory B cells and Ab-secreting plasma cells. The transcription factor IFN regulatory factor 4 (IRF4) is essential for the formation of follicular helper T cells and thus GCs, although whether IRF4 plays a distinct role in GC B cells remains contentious. RNAseq analysis on ex vivo-derived mouse B cell populations showed that Irf4 was lowly expressed in naive B cells, highly expressed in plasma cells, but absent from GC B cells. In this study, we used conditional deletion of Irf4 in mature B cells as well as wild-type and Irf4-deficient mixed bone marrow chimeric mice to investigate how and where IRF4 plays its essential role in GC formation. Strikingly, GC formation was severely impaired in mice in which Irf4 was conditionally deleted in mature B cells, after immunization with protein Ags or infection with Leishmania major. This effect was evident as early as day 5 following immunization, before the development of GCs, indicating that Irf4 was required for the development of early GC B cells. This defect was B cell intrinsic because Irf4-deficient B cells in chimeric mice failed to participate in the GC in response to L. major or influenza virus infection. Taken together, these data demonstrate a B cell-intrinsic requirement for IRF4 for not only the development of Ab secreting plasma cells but also for GC formation.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
authors.forename: Simon N
authors.initials: SN
authors.lastname: Willis
authors.forename: Kim L
authors.initials: KL
authors.lastname: Good-Jacobson
authors.forename: Joan
authors.initials: J
authors.lastname: Curtis
authors.forename: Amanda
authors.initials: A
authors.lastname: Light
authors.forename: Julie
authors.initials: J
authors.lastname: Tellier
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Corcoran
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology / Q000502:physiology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology / Q000502:physiology; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017423:Sequence Analysis, RNA / Q000379:methods; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D000941:Antigens; D050835:Interferon Regulatory Factors; D017455:Receptors, IgE; D000099218:Interferon Regulatory Factor-4