We recently reported that TNFR-associated factor (TRAF)3, a ubiquitously expressed adaptor protein, promotes mature B cell apoptosis. However, the specific function of TRAF3 in T cells has remained unclear. In this article, we report the generation and characterization of T cell-specific TRAF3−/− mice, in which the traf3 gene was deleted from thymocytes and T cells. Ablation of TRAF3 in the T cell lineage did not affect CD4 or CD8 T cell populations in secondary lymphoid organs or the numbers or proportions of CD4+,CD8+ or double-positive or double-negative thymocytes, except that the T cell-specific TRAF3−/− mice had a 2-fold increase in FoxP3+ T cells. In striking contrast to mice lacking TRAF3 in B cells, the T cell TRAF3-deficient mice exhibited defective IgG1 responses to a T-dependent Ag, as well as impaired T cell-mediated immunity to infection with Listeria monocytogenes. Surprisingly, we found that TRAF3 was recruited to the TCR/CD28 signaling complex upon costimulation and that TCR/CD28-mediated proximal and distal signaling events were compromised by TRAF3 deficiency. These findings provide insights into the roles played by TRAF3 in T cell activation and T cell-mediated immunity.

The tumor necrosis factor receptor (TNFR) superfamily molecule CD40 is expressed by a wide variety of cell types following activation signals, and constitutively on B lymphocytes, macrophages, and dendritic cells. CD40 signals to cells stimulate kinase activation, gene expression, production of a antibody and a variety of cytokines, expression or upregulation of surface molecules, and protection or promotion of apoptosis. Initial steps in CD40-mediated signal cascades involve the interactions of CD40 with various members of the TNFR-associated factor (TRAF) family of cytoplasmic proteins. This review summarizes current understanding of the nature of these interactions, and how they induce and regulate CD40 functions.

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The cytoplasmic signaling protein TNF receptor-associated factor 5 (TRAF5) has been implicated in several biological roles in Tlymphocyte responses. However, a clear connection between in vivo TRAF5 immune cell functions and specific signaling pathways has not been made. This study shows that TRAF5 associated strongly with the viral oncogenic CD40 mimic latent membrane protein 1 (LMP1), in contrast to weaker association with CD40, for which it has been shown to play a modest role. LMP1 uses specific TRAFs differently than CD40, resulting in amplified and dysregulated CD40-like activation of B lymphocytes. When the cytoplasmic domain of LMP1 is expressed as a transgenic replacement for CD40 in mouse B cells, the resulting mouse exhibits measures of B-cell hyperactivity such as splenomegaly, lymphadenopathy, elevated serum IL-6, elevated serum autoantibodies, and abnormal splenic architecture. Thus, in contrast to CD40, TRAF5 may have an important nonredundant role as a positive mediator of LMP1 signaling and functions in B cells. To test this hypothesis, mice were created that express mCD40LMP1 in place of CD40, and are either sufficient or deficient in TRAF5. Results revealed that TRAF5 plays a critical role in LMP1-mediated c-Jun kinase signaling and is required for much of the abnormal phenotype observed in mCD40LMP1 transgenic mice. This is the first report showing a major requirement for TRAF5 in signaling by a specific receptor both in vitro and in vivo, as well as playing an important role in biological function in B lymphocytes.B lymphocyte ͉ latent membrane protein 1 ͉ TNF receptor-associated factor ͉ lymphocyte activation ͉ TNF receptor superfamily T he Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) is a functional mimic of CD40 expressed as a six transmembrane receptor on the cell surface (1). LMP1 selfoligomerizes, resulting in constitutive signaling (1, 2). Although LMP1 can initiate signaling without a ligand, the unique nature of its cytoplasmic domain results in sustained and amplified activation independent of its transmembrane regions. Thus, a hybrid molecule in which the transmembrane domains of LMP1 are replaced with the transmembrane and extracellular portions of CD40 induces B-cell activation that is higher and more prolonged than levels achieved by endogenous CD40 (3-5). Expression of LMP1 by B cells also results in increased survival (5, 6) and class switching (7). The heightened activation state caused by LMP1 expression in mice leads to B-cell hyperactivity, resulting in splenomegaly, lymphadenopathy, and production of elevated serum IL-6 and autoantibodies (4). The amplified and constitutive CD40-like signal provided by LMP1 can also contribute to generation of Reed-Sternberg cells (8) and B-cell lymphoma (9).Like CD40, LMP1 binds and uses cytoplasmic adaptor molecules known as TNF receptor-associated factors (TRAFs). Interestingly, LMP1 uses TRAFs 1, 2, and 3 differently than CD40. TRAFs 1 and 2 cooperate to promote certain CD40-mediated signals to B cells, but TRAF3 inhib...

Developing thymocytes and T cells express the Tec kinases Itk, Rlk/Txk and Tec, which are critical modulators of T‐cell receptor signaling, required for full activation of phospholipase Cγ, and downstream Ca2+ and ERK‐mediated signaling pathways. Over the last 10 years, data have implicated the Tec family kinases Itk and Rlk/Txk as important regulators of cytokine production by CD4+ effector T‐cell populations. Emerging data now suggest that the Tec family kinases not only influence cytokine‐producing T‐cell populations in the periphery, but also regulate the development of distinct innate‐type cytokine‐producing T‐cell populations in the thymus. Together, these results suggest that the Tec family kinases play critical roles in helping shape immune responses via their effects on the differentiation and function of distinct cytokine‐producing, effector T‐cell populations.