TRAF3: uncovering the real but restricted role in human

immune deficiency involving a TRAF protein, and show that human immunity to the virus HSV-1 is critically dependent on TRAF3. Tumor necrosis factor (TNF) receptor associated factors (TRAFs) are multi-functional intracellular proteins that recruit and activate protein kinases in immune signaling pathways. The function of many TRAF proteins has been particularly well established in TNF receptor family signaling in B and T lymphocytes, and in pattern recognition receptor (PRR) signaling in antigen presenting cells, mainly through the use of gene deleted mice. For example, TRAF6 has been shown to be critical for signaling by two PRR families, namely the Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), where it controls activation of the transcription factor NF-κB, leading to the production of proinflammatory cytokines. However the function of TRAF3 remained enigmatic until 2006 since Traf3-/- mice die shortly after birth (Xu et al., 1996). In that year, two studies used Traf3-/- myeloid cells to show that TRAF3 was essential for induction of type I interferons (IFNs) in response to all the murine anti-viral nucleic acid sensing TLRs (TLR3, 7, 9), and also for TLR-independent type I IFN induction