| First Author | McPherson AJ | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 27 | Pages | 23010-9 |
| PubMed ID | 22570473 | Mgi Jnum | J:188379 |
| Mgi Id | MGI:5440390 | Doi | 10.1074/jbc.M112.350538 |
| Citation | McPherson AJ, et al. (2012) Opposing roles for TRAF1 in the alternative versus classical NF-kappaB pathway in T cells. J Biol Chem 287(27):23010-9 |
| abstractText | 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-kappaB 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-kappaB 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-kappaB 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-kappaB pathway. We also show that while both TRAF1 and cIAP1 have non-redundant roles in suppressing the alternative NF-kappaB pathway in T cells activated in the absence of costimulation, activation of the classical NF-kappaB 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-kappaB pathway. |
