Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFκB2 signaling that contributes to autoimmunity

Wen Jye Lin, Yu Wen Su, Yong Chen Lu, Zhenyue Hao, Iok In Christine Chio, Nien Jung Chen, Anne Brüstle, Wanda Y. Li, Tak Wah Mak*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


TNF receptor-associated factor 2 (TRAF2) is a key intracellular signaling mediator that acts downstream of not only TNFα but also various members of the TNFα superfamily. Here, we report that, despite their lack of TNFα signaling, TRAF2 -/-TNFα -/- mice develop an inflammatory disorder characterized by autoantibody accumulation and organ infiltration by T cells with the phenotypes of activated, effector, and memory cells. RAG1 -/- mice reconstituted with TRAF2 -/-TNFα -/- bone marrow cells showed increased numbers of hyperactive T cells and rapidly developed progressive and eventually lethal inflammation. No inflammation was observed in RAG1 -/- mice reconstituted with TRAF2 -/-TNFα -/-T-cell receptor β -/- or TRAF2 -/-TNFα -/-NFκB- induced kinase +/- bone marrow cells. The pathogenic TRAF2 -/-TNFα -/- T cells showed constitutive NFκB2p52 activation and produced elevated levels of T-helper 1 and T-helper 17 cytokines. Our results suggest that a regulatory circuit consisting of TRAF2-NFκB-induced kinase- NFκB2p52 is essential for the proper control of effector T-cell polarization and that loss of T-cell TRAF2 function induces constitutive NFκB2p52 activity that drives fatal autoimmune inflammation independently of TNFα signaling. The involvement of this regulatory circuit in controlling autoimmune responses highlights the delicate balance required to avoid paradoxical adverse events when implementing new targeted anti-inflammatory therapies.

Original languageEnglish
Pages (from-to)18354-18359
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - 8 Nov 2011


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