Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T-cell activation is poorly understood. We have shown that naïve T-cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper-1 (Th1) and Th17 cells and attenuated inflammatory T-cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T-cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.

T-cell activation is subject to tight regulation to avoid inappropriate responses against self-antigens. Here we show that genetic deficiency in an ubiquitin ligase, Peli1, causes hyper activation of T cells and renders T cells refractory to suppression by T regulatory cells and transforming growth factor (TGF)-β. As a result, Peli1 knockout mice spontaneously develop autoimmunity, characterized by multiorgan inflammation and autoantibody production. Peli1 deficiency results in accumulation of nuclear c-Rel, a member of the NF-κB family of transcription factors with pivotal roles in T-cell activation. Peli1 negatively regulates c-Rel by mediating its K48 ubiquitination. These results identify Peli1 as a critical factor in the maintenance of peripheral T-cell tolerance and reveal a novel mechanism of c-Rel regulation.

Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here, we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and serves as a pivotal mediator of microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and, thereby, promotes recruitment of T cells into the central nervous system. Peli1-deficient mice are refractory to EAE induction despite their competent production of Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms HHS Public Access

Deubiquitinases (DUBs) represent a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized an E3 ubiquitin ligase, MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.

The noncanonical NF-κB pathway forms a major arm of NF-κB signaling that mediates important biological functions, including lymphoid organogenesis, B lymphocyte function, and cell growth and survival1-3. Activation of the noncanonical NF-κB pathway involves degradation of an inhibitory protein, TNF receptor associated factor 3 (TRAF3), but how this signaling event is controlled is still unknown1,2. Here we have identified the deubiquitinase Otud7b as a pivotal regulator of the noncanonical NF-κB pathway. Otud7b deficiency in mice has no appreciable effect on canonical NF-κB activation but causes hyper-activation of noncanonical NF-κB. In response to noncanonical NF-κB stimuli, Otud7b binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant noncanonical NF-κB activation. Consequently, the Otud7b deficiency results in B-cell hyperresponsiveness to antigens, lymphoid follicular hyperplasia in the intestinal mucosa, and elevated host-defense ability against an intestinal bacterial pathogen, Citrobacter rodentium. These findings establish Otud7b as a crucial regulator of signal-induced noncanonical NF-κB activation and suggest a mechanism of immune regulation that involves Otud7b-mediated deubiquitination and stabilization of TRAF3.