Tumor necrosis factor receptor 1-associated death domain protein (TRADD) is the core adaptor recruited to TNF receptor 1 (TNFR1) upon TNF␣ stimulation. In cells from TRADD-deficient mice, TNF␣-mediated apoptosis and TNF␣-stimulated NF-B, JNK, and ERK activation are defective. TRADD is also important for germinal center formation, DR3-mediated costimulation of T cells, and TNF␣-mediated inflammatory responses in vivo. TRADD deficiency does not enhance IFN␥-induced signaling. Importantly, TRADD has a novel role in TLR3 and TLR4 signaling. TRADD participates in the TLR4 complex formed upon LPS stimulation, and TRADD-deficient macrophages show impaired cytokine production in response to TLR ligands in vitro. Thus, TRADD is a multifunctional protein crucial both for TNFR1 signaling and other signaling pathways relevant to immune responses. TNF ͉ innate immunityT umor necrosis factor alpha (TNF␣) is a pleiotropic cytokine involved in a broad range of biological activities, including inflammation and cell differentiation, survival, and death (1). TNF␣ mediates these activities by engaging two distinct cell surface receptors: TNFR1 and TNFR2. Activation of TNFR1 leads to the recruitment of the intracellular death domain (DD)-containing adaptor TNFR-associated DD protein (TRADD) through a homotypic interaction with DD of TNFR1. On one hand, the recruitment of TRADD can promote the association of the TNFR1 complex with Fas-associated DD (FADD), which induces caspase activation and cell death. On the other hand, TRADD can also recruit receptor-interacting protein kinase 1 (RIP1) and TNFR-associated factor-2 (TRAF2), which trigger NF-B activation, leading to cell survival and proinflammatory responses (1).TRADD was originally identified in a yeast two-hybrid screen performed to identify TNFR1-interacting proteins (2). Intriguingly, TRADD is the first adaptor protein identified that binds directly to the DD of TNFR1 but transduces signals resulting in either apoptosis or NF-B activation (2-4). Indeed, TRADD overexpression in 293T cells activates both apoptotic and cellsurvival signaling pathways (2). In addition to TNFR1, TRADD may mediate signaling downstream of the death receptors (and TNFR superfamily members) DR3 and DR6 (5, 6). As well, recent TRADD knockdown studies have indicated that TRADD may be involved in signaling mediated by receptors unrelated to the TNFR superfamily, such as in IFN␥ receptor (7-9). These findings give tantalizing hints of the potential breadth of TRADD functions.To date, a knockout animal model has yet to be reported for TRADD, even though this important adaptor was identified more than ten years ago. In this study, we generate TRADD knockout mice by using conditional gene targeting and show that not only is TRADD indispensable for TNF␣-induced NF-B activation and apoptosis in vitro and TNF␣-induced inflammatory responses in vivo, but also that this molecule is involved in germinal center (GC) formation, T cell costimulation, and TLR signaling. Our TRADD knockout mice represent a very useful t...

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The bursa of Fabricius is critical to normal B-lymphocyte development in birds. During embryonic life, B-cell precursors migrate to the bursal rudiment and those which have undergone productive V(D)J recombination colonize lymphoid follicles and undergo immunoglobulin V gene diversification by gene conversion. The chicken surface IgM complex appears structurally and functionally equivalent to its mammalian counterpart, with homologs to CD79a and CD79b. Expression of a truncated Igmu chain is sufficient to drive the early stages of B-cell development in the embryo bursa. Bursal cells expressing the truncated mu receptor complex proliferate in bursal follicles, and those which contain V gene rearrangements undergo V gene diversification by gene conversion. The bursa is a gut-associated organ and antigen is focused to bursal lymphoid follicles after hatch. While expression of the truncated mu chain is sufficient to support B-cell development in the embryo, B cells expressing this receptor are rapidly eliminated after hatch. We suggest the possibility that B-cell development in the bursa after hatch is driven by encounter with antigen leading to redistribution of B cells within the lymphoid follicle, B-cell proliferation and V gene repertoire development by gene conversion.