Essential Role of the E3 Ubiquitin Ligase Cbl-b in T Cell Anergy Induction

Jeon, Myung Shin; Atfield, Alex; Venuprasad, K.; Krawczyk, Connie M.; Sarao, Renu; Elly, Chris; Yang, Chun; Arya, Sudha; Bachmaier, Kurt; Su, Leon; Bouchard, Dennis; Jones, R. Brad; Gronski, Matthew A; Ohashi, Pamela S.; Wada, Teiji; Bloom, Debra D.; Fathman, C. Garrison; Liu, Yun‐Cai; Penninger, Josef

doi:10.1016/j.immuni.2004.07.013

Cited by 314 publications

(398 citation statements)

References 32 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: 88%

“…Importantly, these mice are highly susceptible to developing peptide-induced experimental autoimmunity, such as experimental encephalomyelitis [32], arthritis [34] and autoimmune diabetes [45]. In accordance with in vitro data, Cbl-bdeficient mice cannot be tolerized in vivo [34]. More strikingly, Cbl-b-mediated T-cell tolerance determines the survival of the mice upon rechallenge with the same antigen.…”

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

confidence: 58%

“…Cbl-b knockout mice develop spontaneous autoimmunity, characterized by generalized organ infiltration and high serological levels of autoantibodies [33]. Importantly, these mice are highly susceptible to developing peptide-induced experimental autoimmunity, such as experimental encephalomyelitis [32], arthritis [34] and autoimmune diabetes [45]. In accordance with in vitro data, Cbl-bdeficient mice cannot be tolerized in vivo [34].…”

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

confidence: 88%

“…The RING-type E3 ligase Cbl-b (Casitas B-cell lymphoma-b) was the first identified E3 ligase involved in T-cell activation and tolerance in vivo [32][33][34]. Ablation of Cbl-b renders peripheral T cells hyperproliferative and able to be fully activated in the absence of CD28 co-stimulation, suggesting that Cbl-b is a critical modulator of T cells, uncoupling T-cell activation from the requirement of costimulation [32,33,35].…”

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

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: 88%

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

confidence: 58%

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

confidence: 88%

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

confidence: 99%

See 2 more Smart Citations

E3 ubiquitin ligases in T‐cell tolerance

Paolino

Penninger

2009

Eur J Immunol

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“…We speculate that this interaction is mediated by tyrosine residues in the C-terminal tail of SHP-2 that constitute potential binding sites for the atypical SH2 domains of c-Cbl. Both, c-Cbl and Cbl-b, are known to be involved in negative regulation of T cell function [48][49][50][51][52]. However, despite the possible interaction of SHP-2 with c-Cbl and Cbl-b in 293T cells, in WT Th cells we were only able to detect the interaction between SHP-2 and c-Cbl but not Cbl-b (Fig.…”

Section: Discussionmentioning

confidence: 78%

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

Hoff

Brunner‐Weinzierl

2007

Eur J Immunol

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Although phosphatases are key players of intracellular processes, not much is known about the phosphatase SHP-2 during T cell differentiation. Here we show that ectopic over-expression of SHP-2 in primary T helper cells directly reduced the frequency of individual lymphocytes expressing pro-inflammatory cytokines after antigen-specific stimulation by a mechanism impairing activation of protein kinase C. In addition we demonstrate that SHP-2 mediates enhanced migration upon CXCR4 signaling in a G-protein-dependent manner. Most strikingly, SHP-2 mediated a dramatic increase in apoptosis by highly enhanced activation of caspases. Co-immunoprecipitations of SHP-2 and c-Cbl from primary T helper cells demonstrated that SHP-2 strongly interacts with the ubiquitin ligase c-Cbl, indicating that c-Cbl could mediate the negative signals of SHP-2. Our results show that SHP-2 signal transduction regulates central checkpoints of T cell differentiation by the activation of distinct signaling cascades.

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