Document Detail

Opposing roles for TRAF1 in the alternative versus classical NF-κB pathway in T cells.
MedLine Citation:
PMID:  22570473     Owner:  NLM     Status:  MEDLINE    
T cells lacking TRAF1 hyperproliferate in response to T cell receptor signaling but have impaired signaling downstream of specific TNFR family members such as 4-1BB. Here we resolve this paradox by showing that while TRAF1 is required for maximal activation of the classical NF-κB pathway downstream of 4-1BB in primary T cells, TRAF1 also restricts the constitutive activation of NIK in anti-CD3-activated T cells. Activation of the alternative NF-κB pathway is restricted in unstimulated cells by a cIAP1/2:TRAF2:TRAF3:NIK complex. Using knockdown of NIK by siRNA we show that in activated CD8 T cells TRAF1 is also involved in this process and that constitutive activation of the alternative NF-κB pathway is responsible for costimulation independent hyperproliferation and excess cytokine production in TRAF1-deficient CD8 T cells compared with WT CD8 T cells. The T cell costimulatory molecule 4-1BB critically regulates the survival of activated and memory CD8 T cells. We demonstrate that stimulation through 4-1BB induces cIAP1-dependent TRAF3 degradation and activation of the alternative NF-κB pathway. We also show that while both TRAF1 and cIAP1 have non-redundant roles in suppressing the alternative NF-κB pathway in T cells activated in the absence of costimulation, activation of the classical NF-κB pathway downstream of 4-1BB requires TRAF1, whereas cIAP1 plays a redundant role with cIAP2. Collectively these results demonstrate that TRAF1 plays a critical role in regulating T cell activation both through restricting the costimulation independent activation of NIK in activated T cells and by promoting the 4-1BB-induced classical NF-κB pathway.
Ann J McPherson; Laura M Snell; Tak W Mak; Tania H Watts
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-08
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-09-11     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23010-9     Citation Subset:  IM    
Department of Immunology, University of Toronto, Ontario M5S 1A8, Canada.
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MeSH Terms
Antigens, CD137 / immunology,  metabolism
CD8-Positive T-Lymphocytes / cytology,  immunology,  metabolism*
Cell Division / immunology
Lymphocyte Activation / immunology
Mice, Inbred C57BL
Mice, Transgenic
NF-kappa B / metabolism*
Protein-Serine-Threonine Kinases / immunology,  metabolism
Receptors, Cell Surface / genetics,  immunology,  metabolism
Signal Transduction / immunology*
TNF Receptor-Associated Factor 1 / genetics,  immunology*,  metabolism*
Reg. No./Substance:
0/Antigens, CD137; 0/NF-kappa B; 0/Receptors, Cell Surface; 0/TNF Receptor-Associated Factor 1; EC Kinases; EC B kinase

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