| First Author | Lin WJ | Year | 2011 |
| Journal | Proc Natl Acad Sci U S A | Volume | 108 |
| Issue | 45 | Pages | 18354-9 |
| PubMed ID | 22042853 | Mgi Jnum | J:180231 |
| Mgi Id | MGI:5305882 | Doi | 10.1073/pnas.1109427108 |
| Citation | Lin WJ, et al. (2011) Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFkappaB2 signaling that contributes to autoimmunity. Proc Natl Acad Sci U S A 108(45):18354-9 |
| abstractText | TNF receptor-associated factor 2 (TRAF2) is a key intracellular signaling mediator that acts downstream of not only TNFalpha but also various members of the TNFalpha superfamily. Here, we report that, despite their lack of TNFalpha signaling, TRAF2(-/-)TNFalpha(-/-) 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(-/-)TNFalpha(-/-) 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(-/-)TNFalpha(-/-)T-cell receptor beta(-/-) or TRAF2(-/-)TNFalpha(-/-)NFkappaB-induced kinase(+/-) bone marrow cells. The pathogenic TRAF2(-/-)TNFalpha(-/-) T cells showed constitutive NFkappaB2p52 activation and produced elevated levels of T-helper 1 and T-helper 17 cytokines. Our results suggest that a regulatory circuit consisting of TRAF2-NFkappaB-induced kinase-NFkappaB2p52 is essential for the proper control of effector T-cell polarization and that loss of T-cell TRAF2 function induces constitutive NFkappaB2p52 activity that drives fatal autoimmune inflammation independently of TNFalpha 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. |
