TRAF2 deficiency in B cells impairs CD40-induced isotype switching that can be rescued by restoring NF-kB1 activation

Rachel A. Woolaver, Xiaoguang Wang, Yonatan Dollin, Ping Xie, Jing H. Wang, Zhangguo Chen

Research output: Contribution to journalArticle

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Abstract

Effective humoral immunity requires class switch recombination (CSR) catalyzed by activation-induced cytidine deaminase (AID). In response to T cell-dependent (TD) Ags, CSR can be induced by CD40 signaling in B cells. TNFR-associated factors 2 and 3 (TRAF2/TRAF3) function as adaptors of the CD40 signaling pathway. B cell-intrinsic TRAF2 or TRAF3 (B-TRAF2 or B-TRAF3) knockout mice were previously reported to have indistinguishable phenotypes in gene expression, B cell survival and development, and enlarged peripheral lymphoid organs. However, it remains unknown whether deficiency of B-TRAF2 or B-TRAF3 differentially affects TD humoral immune responses and CD40-induced CSR. In this article, we show that B-TRAF2 is essential for optimal isotype switching induced by in vivo TD Ag immunization or by engaging CD40 in vitro. Our data clarify the controversial role of B-TRAF3 and confirm its dispensability in CD40-induced CSR. Mechanistically, CD40-induced AID expression was markedly impaired by B-TRAF2, but not B-TRAF3, deficiency. Moreover, B-TRAF2 deficiency causes defective activation of the NF-kB1 complex in a CD40-autonomous manner, and restoring CD40-induced NF-kB1 activation in TRAF2-deficient B cells rescues AID expression and CSR. We conclude that TRAF2 is essential but TRAF3 is dispensable for TD humoral immunity and CD40-induced CSR. Our studies provide significant biological bases for optimizing treatment of B cell-associated immune disorders by targeting CD40 signaling.

Original languageEnglish (US)
Pages (from-to)3421-3430
Number of pages10
JournalJournal of Immunology
Volume201
Issue number11
DOIs
StatePublished - Dec 1 2018

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TNF Receptor-Associated Factor 2
Immunoglobulin Class Switching
TNF Receptor-Associated Factor 3
B-Lymphocytes
Genetic Recombination
Humoral Immunity
T-Lymphocytes
Immune System Diseases
Knockout Mice
Immunization
Cell Survival

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Woolaver, Rachel A. ; Wang, Xiaoguang ; Dollin, Yonatan ; Xie, Ping ; Wang, Jing H. ; Chen, Zhangguo. / TRAF2 deficiency in B cells impairs CD40-induced isotype switching that can be rescued by restoring NF-kB1 activation. In: Journal of Immunology. 2018 ; Vol. 201, No. 11. pp. 3421-3430.
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abstract = "Effective humoral immunity requires class switch recombination (CSR) catalyzed by activation-induced cytidine deaminase (AID). In response to T cell-dependent (TD) Ags, CSR can be induced by CD40 signaling in B cells. TNFR-associated factors 2 and 3 (TRAF2/TRAF3) function as adaptors of the CD40 signaling pathway. B cell-intrinsic TRAF2 or TRAF3 (B-TRAF2 or B-TRAF3) knockout mice were previously reported to have indistinguishable phenotypes in gene expression, B cell survival and development, and enlarged peripheral lymphoid organs. However, it remains unknown whether deficiency of B-TRAF2 or B-TRAF3 differentially affects TD humoral immune responses and CD40-induced CSR. In this article, we show that B-TRAF2 is essential for optimal isotype switching induced by in vivo TD Ag immunization or by engaging CD40 in vitro. Our data clarify the controversial role of B-TRAF3 and confirm its dispensability in CD40-induced CSR. Mechanistically, CD40-induced AID expression was markedly impaired by B-TRAF2, but not B-TRAF3, deficiency. Moreover, B-TRAF2 deficiency causes defective activation of the NF-kB1 complex in a CD40-autonomous manner, and restoring CD40-induced NF-kB1 activation in TRAF2-deficient B cells rescues AID expression and CSR. We conclude that TRAF2 is essential but TRAF3 is dispensable for TD humoral immunity and CD40-induced CSR. Our studies provide significant biological bases for optimizing treatment of B cell-associated immune disorders by targeting CD40 signaling.",
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TRAF2 deficiency in B cells impairs CD40-induced isotype switching that can be rescued by restoring NF-kB1 activation. / Woolaver, Rachel A.; Wang, Xiaoguang; Dollin, Yonatan; Xie, Ping; Wang, Jing H.; Chen, Zhangguo.

In: Journal of Immunology, Vol. 201, No. 11, 01.12.2018, p. 3421-3430.

Research output: Contribution to journalArticle

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T1 - TRAF2 deficiency in B cells impairs CD40-induced isotype switching that can be rescued by restoring NF-kB1 activation

AU - Woolaver, Rachel A.

AU - Wang, Xiaoguang

AU - Dollin, Yonatan

AU - Xie, Ping

AU - Wang, Jing H.

AU - Chen, Zhangguo

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