title: Dissection of B cell differentiation during primary immune responses in mice with altered CD40 signals.
abstract: CD40 is essential for efficient humoral immune responses. CD40 has two cytoplasmic domains required for binding of tumor necrosis factor receptor-associated factors (TRAF). The TRAF6-binding site is within the membrane proximal cytoplasmic (Cmp) region, while a PXQXT motif in the membrane distal cytoplasmic (Cmd) region needs to engage TRAF2/3/5. To dissect CD40 signals necessary for B cell differentiation, we generated transgenic mice expressing wild-type and mutant human CD40 (hCD40) molecules in a mouse CD40-deficient (mCD40(-/-)) background. The B cell-specific expression of hCD40 in mCD40(-/-) mice resulted in T-dependent antibody responses including germinal center (GC) formation. Mutant hCD40 molecules that carry either a point mutation of the TRAF2/3/5-binding site or a deletion of the Cmd region rescued extrafollicular B cell differentiation but not GC formation. A mutant hCD40 that comprises of only the TRAF2/3/5-binding site in the cytoplasmic region also rescued low but significant titers of antigen-specific IgG1 without GC formation. These results demonstrated that two distinct signals either from the Cmp or from the Cmd region induced the extrafollicular B cell differentiation and Ig class switching; however, GC formation required both. We conclude that combinations of these two signals determine which of the extrafollicular or the follicular (GC) differentiation pathway B cells enter.
authors.affiliation: Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yasui
authors.forename: Masaaki
authors.initials: M
authors.lastname: Muraoka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takaoka-Shichijo
authors.forename: Isao
authors.initials: I
authors.lastname: Ishida
authors.forename: Noriko
authors.initials: N
authors.lastname: Takegahara
authors.forename: Junji
authors.initials: J
authors.lastname: Uchida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.forename: Sachiko
authors.initials: S
authors.lastname: Suematsu
authors.forename: Misao
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology; D017578:Immunoglobulin Class Switching; D007136:Immunoglobulins / Q000096:biosynthesis; D007150:Immunohistochemistry; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048015:TNF Receptor-Associated Factor 5
chemical_list: D019013:CD40 Antigens; D007136:Immunoglobulins; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048015:TNF Receptor-Associated Factor 5