title: Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination.
abstract: Switched antibody classes are important for efficient immune responses. Aberrant antibody production to otherwise harmless antigens may result in autoimmunity. The protein kinase fms-like tyrosine kinase 3 receptor (Flt3) has an important role during early B-cell development, but the role of Flt3 in peripheral B cells has not been assessed before. Herein we describe a previously unappreciated role for Flt3 in IgG1 class-switch recombination (CSR) and production. We show that Flt3 is reexpressed on B-cell lymphoma 6(+) germinal center B cells in vivo and following LPS activation of peripheral B cells in vitro. Absence of Flt3 signaling in Flt3 ligand-deficient mice results in impaired IgG1 CSR and accumulation of IgM-secreting plasma cells. On activated B cells, Flt3 is coexpressed and functions in synergy with the common-gamma chain receptor family. B cells from Flt3 ligand-deficient mice have impaired IL-4R signaling, with reduced phosphorylation of signal transducer and activator of transcription (Stat) 6, and demonstrate a failure to initiate CSR to IgG1 with low expression of γ1 germ-line transcripts, resulting in impaired IgG1 production. Thus, functional synergy between Flt3 and IL-4R signaling is critical for Stat-mediated regulation of sterile γ1 germ-line transcripts and CSR to IgG1.
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden; mattias.svensson@rheuma.gu.se.
authors.forename: Mattias N D
authors.initials: MN
authors.lastname: Svensson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden;
authors.forename: Karin M E
authors.initials: KM
authors.lastname: Andersson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden;
authors.forename: Caroline
authors.initials: C
authors.lastname: Wasén
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden;
authors.forename: Malin C
authors.identifier: http://orcid.org/0000-0003-1100-7577
authors.initials: MC
authors.lastname: Erlandsson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden;
authors.forename: Merja
authors.initials: M
authors.lastname: Nurkkala-Karlsson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden;
authors.forename: Ing-Marie
authors.initials: IM
authors.lastname: Jonsson
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden;
authors.forename: Mikael
authors.initials: M
authors.lastname: Brisslert
authors.affiliation: Department of Microbiology and Immunology at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41390, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Bemark
authors.affiliation: Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden;
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology*; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000276:immunology*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000502:physiology*
chemical_list: D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008024:Ligands; D019948:Receptors, Interleukin-4; C033027:secretory IgM; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3
keywords: Flt3; IL-4R; IgG1; class-switch recombination; germinal center B cells