TRANCE (Tumor necrosis factor [TNF]-related Activation-induced Cytokine), a new TNF family member predominantly expressed in t cells, is a dendritic cell-specific survival factor

TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine) is a new member of the TNF family that is induced upon T cell receptor engagement and activates c-Jun N-terminal kinase (JNK) after interaction with its putative receptor (TRANCE-R). In addition, TRANCE expression is restricted to lymphoid organs and T cells. Here, we show that high levels of TRANCE-R are detected on mature dendritic cells (DCs) but not on freshly isolated B cells, T cells, or macrophages. Signaling by TRANCE-R appears to be dependent on TNF receptor-associated factor 2 (TRAF2), since JNK induction is impaired in cells from transgenic mice overexpressing a dominant negative TRAF2 protein. TRANCE inhibits apoptosis of mouse bone marrow-derived DCs and human monocyte-derived DCs in vitro. The resulting increase in DC survival is accompanied by a proportional increase in DC-mediated T cell proliferation in a mixed leukocyte reaction. TRANCE upregulates Bcl-X(L) expression, suggesting a potential mechanism for enhanced DC survival. TRANCE does not induce the proliferation of or increase the survival oft or B cells. Therefore, TRANCE is a new DC-restricted survival factor that mediates T cell-DC communication and may provide a tool to selectively enhance DC activity

Differential regulation of IL-22BP in Crohn’s disease versus ulcerative colitis

International audienc

TRANCE, a tumor necrosis factor family member critical for CD40 ligand- independent T helper cell activation

CD40 ligand (CD40L), a tumor necrosis factor (TNF) family member, plays a critical role in antigen-specific T cell responses in vivo. CD40L expressed on activated CD4+ T cells stimulates antigen-presenting cells such as dendritic cells, resulting in the upregulation of costimulatory molecules and the production of various inflammatory cytokines required for CD4+ T cell priming in vivo. However, CD40L- or CD40-deficient mice challenged with viruses mount protective CD4+ T cell responses that produce normal levels of interferon γ, suggesting a CD40L/CD40-independent mechanism of CD4+ T cell priming that to date has not been elucidated. Here we show that CD4+ T cell responses to viral infection were greatly diminished in CD40-deficient mice by administration of a soluble form of TNF-related activation-induced cytokine receptor (TRANCE-R) to inhibit the function of another TNF family member, TRANCE. Thus, the TRANCE/TRANCE-R interaction provides costimulation required for efficient CD4+ T cell priming during viral infection in the absence of CD40L/CD40. These results also indicate that not even the potent inflammatory microenvironment induced by viral infections is sufficient to elicit efficient CD4+ T cell priming without proper costimulation provided by the TNF family (CD40L or TRANCE). Moreover, the data suggest that TRANCE/TRANCE-R may be a novel and important target for immune intervention

The TRAF family of signal transducers mediates NF-κB activation by the TRANCE receptor

Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a member of the TNF family expressed on activated T-cells, bone marrow stromal cells, and osteoblasts, regulates the function of dendritic cells (DC) and osteoclasts. The TRANCE receptor (TRANCE-R), recently identified as receptor activator of NF-κβ (RANK), activates NF-κB, a transcription factor critical in the differentiation and activation of those cells. In this report we identify the TNF receptor-associated factor (TRAF) family of signal transducers as important components of TRANCE-R-mediated NF- κB activation. Coimmunoprecipitation experiments suggested potential interactions between the cytoplasmic tail of TRANCE-R with TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6. Dominant negative forms of TRAF2, TRAF5, and TRAF6 and an endogenous inhibitor of TRAF2, TRAF-interacting protein (TRIP), substantially inhibited TRANCE-R-mediated NF-κB activation, suggesting a role of TRAFs in regulating DC and osteoclast function. Overexpression of combinations of TRAF dominant negative proteins revealed competition between TRAF proteins for the TRANCE-R and the possibility of a TRAF-independent NF- κB pathway. Analysis of TRANCE-R deletion mutants suggested that the TRAF2 and TRAF5 interaction sites were restricted to the C-terminal 93 amino acids (C-region). TRAF6 also complexed to the C-region in addition to several regions N-terminal to the TRAF2 and TRAF5 association sites. Furthermore, transfection experiments with TRANCE-R deletion mutants revealed that multiple regions of the TRANCE-R can mediate NF-κB activation

A subset of dendritic cells as a major and constitutive source of IL-22BP

Poster presentationInternational audienc

Penicillin Binding Proteins as Danger Signals: Meningococcal Penicillin Binding Protein 2 Activates Dendritic Cells through Toll-Like Receptor 4

Neisseria meningitidis is a human pathogen responsible for life-threatening inflammatory diseases. Meningococcal penicillin-binding proteins (PBPs) and particularly PBP2 are involved in bacterial resistance to β-lactams. Here we describe a novel function for PBP2 that activates human and mouse dendritic cells (DC) in a time and dose-dependent manner. PBP2 induces MHC II (LOGEC50 = 4.7 µg/ml±0.1), CD80 (LOGEC50 = 4.88 µg/ml±0.15) and CD86 (LOGEC50 = 5.36 µg/ml±0.1). This effect was abolished when DCs were co-treated with anti-PBP2 antibodies. PBP2-treated DCs displayed enhanced immunogenic properties in vitro and in vivo. Furthermore, proteins co-purified with PBP2 showed no effect on DC maturation. We show through different in vivo and in vitro approaches that this effect is not due to endotoxin contamination. At the mechanistic level, PBP2 induces nuclear localization of p65 NF-kB of 70.7±5.1% cells versus 12±2.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed tha