Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins

Heissmeyer, Vigo; Macián, Fernando; Im, Sin Hyeog; Varma, Rajat; Feske, Stefan; Venuprasad, K.; Gu, Hua; Liu, Yun‐Cai; Dustin, Michael L.; Rao, Anjana

doi:10.1038/ni1047

Cited by 484 publications

(600 citation statements)

References 52 publications

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“…In accordance with early studies showing Cbl-b upregulation in anergized T cells, Cbl-b À/À T cells are resistant to ionomycin-induced anergy [34,40]. Under anergic conditions, Cbl-b upregulation correlates with PLCg1 and PKCy ubiquitylation and an ensuing calcium mobilization defect, suggesting these two molecules may be crucial targets for Cbl-b anergic functions [34,40].…”

Section: Physiological and Molecular Roles Of E3 Ligases In T-cell Tosupporting

confidence: 87%

“…Beside its role in T-cell differentiation, Itch has also been implicated in the regulation of T-cell tolerance. As in the case of Cbl-b, Itch is upregulated in vitro under anergizing stimuli [40]. In accordance, Itch À/À Th2 cells are resistant to ionomycin-induced anergy as well as high doses of tolerizing antigen in a mouse model for asthmatic airway inflammation [51].…”

Section: Physiological and Molecular Roles Of E3 Ligases In T-cell Tomentioning

confidence: 68%

“…As its name suggests, Grail was identified as a transcript highly upregulated in anergized T cells [40,53]. Subsequent studies confirmed its upregulation in different models of in vivo adaptive tolerance, and further showed that constitutive expression of Grail was sufficient to render the transduced T cells anergic [54].…”

Section: Grailmentioning

confidence: 99%

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E3 ubiquitin ligases in T‐cell tolerance

Paolino

Penninger

2009

Eur J Immunol

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The immune system uses several mechanisms of central and peripheral tolerance in order to prevent the activation of T lymphocytes toward self-antigens. Although the importance of immune self-tolerance has been established for a long time, some essential cellular and molecular mechanisms of T-cell tolerance have only been recently revealed. Once thought to be a recycling system, protein ubiquitylation by E3 ligases has now emerged as a regulated and crucial modulator of immune responses, and more importantly as a key signaling pathway involved in T-cell tolerance. In this review, we highlight our current understanding of the transcriptional and molecular signaling mechanisms involved in ubiquitylation-mediated T-cell tolerance.Key words: Autoimmunity . Cbl-b . E3 ligase . T-cell tolerance . Ubiquitylation IntroductionUpon activation, the immune system orchestrates robust and potentially destructive responses intended to eliminate the immunogenic antigen. Thus, immune system activation is under stringent control to prevent a detrimental immune response against self-antigens. The processes that ensure unresponsiveness toward self-antigens are known as immunological tolerance and, in their absence or failure, autoimmunity occurs [1]. Central tolerance mechanisms operate in the thymus to eliminate potentially self-reactive thymocytes and generate (T reg ) suppressor cells [2]. In addition, several peripheral tolerance mechanisms act to prevent self-reactivity once mature T cells have reached the periphery. These peripheral mechanisms of tolerance include the following: (i) immunological ignorance to selfantigens expressed at low levels or in immunoprivileged sites; (ii) active immunosuppression by Foxp31 T reg cells; (iii) activation-induced cell death of autoreactive T cells and (iv) induction of a state of unresponsiveness known as T-cell anergy [3].During the past few years, extensive research has revealed new insights into the cellular and molecular mechanisms necessary to induce and maintain T-cell tolerance. In particular, ubiquitylation of proteins by E3 ligases has emerged as a novel and indispensable signaling pathway that regulates T-cell tolerance toward self-antigens [4][5][6]. The ubiquitylation processUbiquitylation is an important mechanism of post-translational modification of proteins by which the 76-aa polypeptide ubiquitin, Ub, is covalently attached to a substrate protein. This process occurs in a stepwise manner, requiring the participation of three enzymes: a ubiquitin-activating enzyme E1, responsible for the first binding and activation of the Ub; a second ubiquitinconjugating enzyme E2, which receives the activated Ub from the E1; and a third ubiquitin-ligase E3 that catalyzes the final covalent transfer of the Ub from the E2 enzyme to the protein substrate [7]. Once thought to only mediate proteosomal degradation, the ubiquitylation of a protein can have multiple effects, including altered subcellular localization, regulation of protein-protein interactions, and functional modulation. The fa...

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Section: Physiological and Molecular Roles Of E3 Ligases In T-cell Tosupporting

confidence: 87%

Section: Physiological and Molecular Roles Of E3 Ligases In T-cell Tomentioning

confidence: 68%

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E3 ubiquitin ligases in T‐cell tolerance

Paolino

Penninger

2009

Eur J Immunol

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“…Our data that both Egr-2 and Egr-3 are upregulated by ionomycin alone and that their induction is not dependent upon MAP-kinase activation support this hypothesis. Of interest, it has been proposed that the upregulation of the E3 ligases represents an important component of NF-AT-induced inhibition [30]. Previously, we have shown that the E3 ligase Cbl-b is decreased in T cells from Egr-3 null mice and increased with the overexpression of Egr-3.…”

Section: Discussionmentioning

confidence: 80%

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

et al. 2008

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TCR-induced NF-AT activation leads to the up-regulation of multiple genes involved in T cell anergy. Since NF-AT is also involved in T cell activation, we have endeavored to dissect TCR-induced activating and inhibitory genetic programs. This approach revealed roles for the early growth response (Egr) family of transcription factors and the Egr coactivator/corepressor NGFI-A-binding protein (NAB)2 in regulating T cell function. TCR-induced Egr-1 and NAB2 enhance T cell function, while Egr-2 and Egr-3 inhibit T cell function. In this report, we demonstrate that Egr-2 and Egr-3 are induced by NF-AT in the absence of AP-1, while Egr-1 and NAB2 both require AP-1-mediated transcription. Our data suggest that Egr-3 is upstream of Egr-2, and that mechanistically Egr-2 and Egr-3 suppress Egr-1 and NAB2 expression. Functionally, T cells from Egr-2 and Egr-3 null mice are hyperresponsive while T cells from Egr-3 transgenic, overexpressing mice are hyporesponsive. Furthermore, an in vivo model of autoimmune pneumonitis reveals that T cells from Egr-3 null mice hasten death while Egr-3-overexpressing T cells cause less disease. Overall, our data suggest that just as the Egr/NAB network of genes control cell fate in other systems, TCR-induced Egr-1, 2, 3 and NAB2 control the fate of antigen recognition in T cells.

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“…79 The NFAT target genes include the RING E3 ligases Cbl-b and GRAIL, as well as the HECT E3 Itch and Nedd4. 80 TCR/CD28 restimulation of 'TCR-only' treated T cells promotes the execution of the anergic gene program. Just like in naïve T cells upon a first encounter with an antigen, primary SMAC formation is not affected in anergic T cells, but the SMACs are highly unstable and the synapse collapses within minutes after engagement.…”

Section: Cd28 Sets the Threshold: The Role Of Ubiquitin Ligasesmentioning

confidence: 99%

Controlling NF-κB activation in T cells by costimulatory receptors

Schmitz

Krappmann

2006

Cell Death Differ

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Full and productive activation of T lymphocytes relies on the simultaneous delivery of T cell receptor (TCR)-and coreceptor-derived signals. In naïve T cells engagement of the TCR alone causes anergy, while TCR triggering of preactivated T cells results in activation-induced cell death. Costimulatory signals are prominently mirrored by the activation of NF-kB, which needs input from the TCR as well as from coreceptors in order to be fully activated and to fulfil its crucial function in the immune response. Coreceptorgenerated signals tightly control the duration and amplitude of the NF-kB response. The activation of IkB kinase (IKK) complex at the contact zone between a T cell and an antigenpresenting cell offers the unique opportunity to study the spatial organization of IKK activation. Recent studies indicate that coreceptor pathways influence the threshold activities of many signalling mediators and thus act on multiple layers of the NF-kB pathway.

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Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins

Cited by 484 publications

References 52 publications

E3 ubiquitin ligases in T‐cell tolerance

E3 ubiquitin ligases in T‐cell tolerance

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

Controlling NF-κB activation in T cells by costimulatory receptors

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