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International Immunology, Vol. 14, No. 3, 319-329, March 2002
© 2002 Japanese Society for Immunology

Dissection of B cell differentiation during primary immune responses in mice with altered CD40 signals

Teruhito Yasui1, Masaaki Muraoka1, Yuko Takaoka-Shichijo1, Isao Ishida1, Noriko Takegahara1, Junji Uchida1, Atsushi Kumanogoh1, Sachiko Suematsu2, Misao Suzuki3 and Hitoshi Kikutani1

1 Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
2 Department of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
3 Division of Transgenic Technology, Center for Animal Resources and Development (CARD), Kumamoto University, Kumamoto 860-0811, Japan.

Correspondence to: H. Kikutani; E-mail: kikutani{at}ragtime.biken.osaka-u.ac.jp

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.

Keywords: B lymphocyte, germinal center, Ig class switching, signal transduction, tumor necrosis factor receptor-associated factor, transgenic mouse

Transmitting editor: T. Watanabe


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