Cutting Edge Contrasting Roles of TNF ReceptorAssociated Factor 2 (TRAF2)… — Volkswagen Santana Variant II

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Volkswagen Santana Variant II


In B lymphocytes, CD40 contribute to the activation of Ab secretion, switching, T cell costimulation, and memory. TRAF proteins to be important components of the CD40 transduction complex, but their in the activation of B cell effector are poorly understood. We examined the of TNF receptor-associated factor 2 (TRAF2) and to CD40-activated differentiation in mouse B transfected with inducible and dominant-negative TRAF cDNAs. We that binding of TRAF2 and to CD40 is not required for the induction of Ab but that both TRAF can regulate the activation process. We a negative regulatory role for and that this activity is on the availability of an intact TRAF3-binding in the cytoplasmic domain of CD40. In TRAF2 appears to play a role in B cell differentiation, and activity is apparent even its binding site on CD40 is


Engagement of CD40 by its on activated T cells initiates in B lymphocytes that contribute to the of cell proliferation, differentiation, switching, enhanced Ag presentation, and events necessary for an efficient immune response (1 ). The CD40 transduction pathway is only characterized but appears to involve members of the TNF receptor-associated factor 3 family of proteins. TRAF2, -3, -5, and -6 all interact with CD40 (2. 3. 4. 5 ), but roles in CD40 signaling are TRAF2 (2 ) and TRAF6 (5 ) can induce the of NF-κB when transiently in the transformed human kidney line 293. In B cell however, mutant CD40 that cannot bind remain able to

activate NF-κB (6 ). In addition, from mice expressing a TRAF2 (DNTRAF2) transgene do not defects in CD40- or TNF receptor-induced activation (7 ), and fibroblast cell isolated from TRAF2-deficient embryos (8 ) exhibit only delays in TNF-induced NF-κB However, lymphocytes from mice and TRAF2-deficient fibroblasts do defects in the activation of c-Jun NH 2 kinase mediated by TNFR members.

The contribution of TRAF3 to CD40 is more enigmatic. Mice in TRAF3 die shortly after (9 ). However, B cells from mice appear to up-regulate and proliferate normally in response to engagement. Fetal liver from TRAF3-deficient mice been used to reconstitute the systems of irradiated wild-type Immune responses in the reconstituted appear grossly normal, there is a defect in isotype in response to T-dependent Ags. with TRAF3 in epithelial lines suggest that can inhibit CD40-mediated NF-κB (2. 10 ).

Although transiently transfected cell lines have useful in the preliminary characterization of the proteins, functional studies been limited to examining the of TRAF (or DNTRAF) overproduction on signaling events, such as activation. To examine the roles of in hemopoietic cells, and specifically roles in B lymphocyte effector we have used inducible vectors to stably transfect B cell lines with and mutant TRAF molecules. We that the binding of TRAF2 or is unnecessary for the ability of CD40 to Ab secretion. However, both molecules can strongly modulate CD40-mediated effector function, and appear to exert their at separate steps in the activation

Materials and Methods

DNA constructs



Stable of mouse B cell lines conducted using electroporation as (14 ). Transient transfection of 293T was accomplished using a calcium method (17 ).

Immunoprecipitations and Western blotting


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