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Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18354-9. doi: 10.1073/pnas.1109427108. Epub 2011 Oct 31.

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

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1
Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2M9.

Abstract

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.

PMID:
22042853
PMCID:
PMC3215017
DOI:
10.1073/pnas.1109427108
[Indexed for MEDLINE]
Free PMC Article
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