Dissection of B cell differentiation during primary immune responses in mice with altered CD40 signals.
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.
Yasui
Teruhito
T
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Muraoka
Masaaki
M
Takaoka-Shichijo
Yuko
Y
Ishida
Isao
I
Takegahara
Noriko
N
Uchida
Junji
J
Kumanogoh
Atsushi
A
Suematsu
Sachiko
S
Suzuki
Misao
M
Kikutani
Hitoshi
H
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
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