Corcoran K et al

Corcoran K et al. (PD-1, BTLA, or TIM3) receptors on T cells (reviewed in [19]). For example TCR/MHC-peptide engagement paired with CD28/B7 costimulation initiates calcineurin, Ras, and PKC- signaling that activates NFAT, AP1, and NF-B transcription factors required to induce IL-2 production, T cell proliferation and differentiation (Figure 1B). In contrast, T cells with TCR/MHC-peptide engagement in the absence of CD28/B7 costimulatory signals do not upregulate IL-2 and enter anergy MT-7716 free base [12] (Figure 1B). Several E3s are transcriptionally upregulated under anergic conditions, among them Cbl-b, Itch, and Grail (also known as RNF128) [20C22], which function to limit TCR signaling output. This is achieved through proteolysis-dependent mechanisms, such as ubiquitin-dependent TCR/CD3 receptor downmodulation by Cbl-b [23] and Grail [24] or downregulation of downstream TCR signaling components including PLC- and PKC- by Itch and MT-7716 free base GLUR3 Cbl-b [20, 25]. Itch further regulates AP1 by proteasomal degradation of junB, a mechanism involved in CTLA-4-mediated T cell inhibition [26, 27]. Cbl-b and Grail also exhibit proteolysis-independent functions that promote anergy: Cbl-b inhibits recruitment of the phosphoinositide 3-kinase subunit p85 to CD28 and TCR [28], preventing TCR clustering [29], and Grail ubiquitination of Rho GDP-dissociation inhibitor stabilizes it, preventing IL-2 expression [30]. Thus, by modulating the abundance/activity of critical TCR signaling molecules, E3s serve as T cell intrinsic checkpoints to limit T cell activation. These molecular mechanisms partially explain spontaneous autoimmunity or enhanced experimentally-induced autoimmunity observed in mice deficient for Cbl-b, Itch, or Grail [24, 31C34] (Table 1) and may serve to develop targeted therapeutics for patients suffering multisystem autoimmune disease, mediated e.g. by polymorphisms in the human homolog of Itch [35]. Interestingly, overstimulated of MT-7716 free base T cells by the effector cytokine IL-2 MT-7716 free base results in co-expression of the apoptosis-related factors Fas (CD95) and Fas ligand (FasL). Engagement of Fas by FasL induces T cell apoptosis, thereby providing an additional safety mechanism to prevent T cell overactivation and mice with defects in Fas, FasL or IL-2R develop autoimmunity due to failure of T cells to undergo AICD [15, 36]. Among E3s that either stimulate or inhibit AICD are WWP2 [37], c-Cbl [38], and A20 [38]. WWP2 limits AICD in T cells by ubiquitinating and destabilizing the transcription factor EGR2, thereby limiting EGR2-mediated FasL upregulation to promotes T cell survival [37]. As A20 has been implicated in the control of RIPK and NF-B signaling, the role of A20 in AICD [38] and its contribution to the phenotypes observed in A20 knockout mice, which exhibit multi-organ inflammation [39] and in men with A20 polymorphisms that are associated with systemic lupus erythematous, Crohns disease or psoriasis [40] remain to be determined. In addition to nTregs that are selected in thymus [15], immunosuppressive Treg can also emerge from na?ve CD4+ T cells following TCR activation in the presence of the suppressor cytokine TGF- [41C43] secreted by tolerogenic DCs [44]; this Treg subset is called induced (i)Treg. The immunosuppressive function of Treg is crucial for tolerance induction, and decreased Treg number or function is associated with a variety of autoimmune pathologies [45]. Interestingly, E3s are implicated in both Treg development and function. For example, Stub1 and Cbl-b activity destabilizes Foxp3, which is required for Treg identity, by ubiquitin-dependent degradation [46, 47]. The E3s von Hippel-Lindau (VHL) and Itch support maintenance of functional Treg [48, 49]. Treg-specific loss of VHL results in HIF1-dependent conversion of Treg into TH1-like, IFN-producing effector T cells, which culminates in multi-organ lymphocyte infiltration and early mouse mortality [48]. Additionally, in an adoptive transfer murine colitis model, VHL-deficient Tregs were unable to prevents colitis, further exemplifying their role in autoimmunity [48]. Similar, Treg-specific Itch deficiency in mice results in severe airway inflammation, mediated by increased TH2 cytokine production by Itch-deficient Tregs [49]. Furthermore, Grail is critical for MT-7716 free base Treg function, as Grail?/? Treg are less immunosuppressive, and express TH17 cell-related genes [24]. Given the crucial role of E3s in maintaining Treg homeostasis, along with their ability to induce anergy in self-reactive T cells, they serve as critical T cell checkpoints to maintain T cell tolerance, thereby preventing autoimmunity. We note that B cells play an equally important role in autoimmunity (recently reviewed [50]) and point to the fact that E3s are crucial regulators of B cell reponses (Table 1; Box 3). Box 3: E3 ubiquitin ligases in B cell tolerance While.