Background: TRAF6, a member of the tumour necrosis factor receptor-associated factor family, was first identified as a transducer of CD40 and interleukin-1 receptor (IL-1R) signals based on the interaction of TRAF6 with the cytoplasmic tail of CD40 and with the IL-1R associated kinase in vitro. However, the functions of TRAF6 in vivo remain unidentified.

Studies performed during the past several years make plain that ligand occupancy of antigen receptors need not necessarily provoke identical responses in all instances. For example, ligation of antigen receptors may stimulate a proliferative response, induce a state of unresponsiveness to subsequent stimulation (anergy), or induce apoptosis. How does a single type of transmembrane receptor induce these very heterogeneous cellular responses? In the following pages, we outline evidence supporting the view that the nature of the ligand/receptor interaction directs the physical recruitment of signaling pathways differentially inside the lymphocyte and hence defines the nature of the subsequent immune response. We begin by providing a functional categorization of antigen receptor components, considering the ways in which these components interact with the known set of signal transduction pathways, and then review the evidence suggesting that differential signaling through the TCR is achieved by qualitative differences in the effector pathways recruited by TCR, perhaps reflecting the time required to bring complicated signal transduction elements into proximity within the cell. The time-constant of the interaction between antigen and receptor in this way determines, at least in part, the nature of the resulting response. Finally, although our review focuses substantially on T cell receptor signaling, we have included a less detailed description of B cell receptor signaling as well, simply to emphasize the parallels that exist in these two closely related systems.

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CD4+ Th1 cells play a critical role in the induction of cell-mediated immune responses that are important for the eradication of intracellular pathogens. Peptide-25 is the major Th1 epitope for Ag85B of Mycobacterium tuberculosis and is immunogenic in I-Ab mice. To elucidate the role of the TCR and IFN-gamma/IL-12 signals in Th1 induction, we generated TCR transgenic mice (P25 TCR-Tg) expressing TCR alpha- and beta-chains of Peptide-25-reactive cloned T cells and analyzed Th1 development of CD4+ T cells from P25 TCR-Tg. Naive CD4+ T cells from P25 TCR-Tg differentiate into both Th1 and Th2 cells upon stimulation with anti-CD3. Naive CD4+ T cells from P25 TCR-Tg preferentially develop Th1 cells upon Peptide-25 stimulation in the presence of I-Ab splenic antigen-presenting cells under neutral conditions. In contrast, a mutant of Peptide-25 can induce solely Th2 differentiation. Peptide-25-induced Th1 differentiation is observed even in the presence of anti-IFN-gamma and anti-IL-12. Furthermore, naive CD4+ T cells from STAT1 deficient P25 TCR-Tg also differentiate into Th1 cells upon Peptide-25 stimulation. Moreover, Peptide-25-loaded I-Ab-transfected Chinese hamster ovary cells induce Th1 differentiation of naive CD4+ T cells from P25 TCR-Tg in the absence of IFN-gamma or IL-12. These results imply that interaction between Peptide-25/I-Ab and TCR may primarily influence determination of the fate of naive CD4+ T cells in their differentiation towards the Th1 subset.