Ubiquitination of key signaling in anergic T cells. (a) Il2 gene transactivation in normal T cells. TCR and CD28 signaling cascades synergistically activate phospholipase C (PLC)γ, PKCθ, Vav, and p85, which are responsible for the induction of transcription factors such as nuclear factor of activated T cells (NF-AT), activating protein 1 (AP-1: Fos and Jun), and nuclear factor κB (NFκB) leading to Il2 gene transcription. (b) Sequestration or degradation of signaling intermediates in activated anergic T cells. Upon stimulation of anergic T cells, increased Cbl-b, Itch, and Nedd4 E3 ligase activities antagonize the normal function of the TCR, Vav, and p85, perhaps sequestering them within an endocytic pathway. Additionally, PLCγ and PKCθ appear to be ubiquitinated and degraded within an endosomal/lysosomal compartment during activation.Ub, ubiquitin.