TRAF1 is a negative regulator of TNF signaling: Enhanced TNF signaling in TRAF1-deficient mice

TNF receptor-associated factor 1 (TRAF1) is a unique TRAF protein because i t lacks a RING finger domain and is predominantly expressed in activated ly mphocytes. To elucidate the function of TRAF1, we generated TRAF1-deficient mice. TRAF1(-/-) mice are viable and have normal lymphocyte development. T RAF1(-/-) T cells exhibit stronger than wild-type (WT) T cell proliferation to anti-CD3 mAb, which persisted in the presence of IL-2 or anti-CD28 anti bodies. Activated TRAF1(-/-) T cells, but not TRAF1(+/+) T cells, responded to TNF by proliferation and activation of the NF-kappaB and AP-1 signaling pathways. This TNF effect was mediated by TNFR2 (p75) but not by TNFR1 (p5 5). Furthermore, skin from TRAF1(-/-) mice was hypersensitive to TNF-induce d necrosis. These findings suggest that TRAF1 is a negative regulator of TN F signaling.