Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation

Fang, Deyu; Elly, Chris; Gao, Baixue; Fang, Nan; Altman, Yoav; Joazeiro, Claudio A.P.; Hunter, Tony; Copeland, Neal G.; Jenkins, Nancy A.; Liu, Yun‐Cai

doi:10.1038/ni763

Cited by 310 publications

(389 citation statements)

References 30 publications

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“…Thus, the decreased FynT activation in the absence of SAP might exert less negative regulation on Itch function, which targets increased ubiquitination and subsequent degradation of p73. The fact that Itch -/-T cells are biased toward Th2 responses further supports the hypothesis that Itch could play an important role in the regulation of T cell apoptosis [47]. It will be interesting to investigate the p73 protein turnover rate in the activated SAP -/-CD8 + T cells, in order to elucidate whether the p73 protein degradation pathway is affected in the mutant cells.…”

Section: Discussionmentioning

confidence: 65%

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

et al. 2007

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Defective signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is responsible for the human X-linked lymphoproliferative syndrome. Defects in T helper 2, natural killer, natural killer T and B cells have been demonstrated in SAP-deficient humans and mice, and increased proliferation of CD8 + T cells has been observed. In the current study, we investigated the properties of CD8 + T cell proliferation and activation-induced cell death (AICD), using OT-I T cell receptor (TCR)-transgenic mice on either wild-type (WT) or SAP -/-background. Interestingly, we found that ovalbumin peptide-activated SAP -/-CD8 + T cells have lower AICD compared to their WT counterparts. Furthermore, the induction of p73, a key mediator of TCRinduced apoptosis through the mitochondrial apoptotic pathway, was significantly reduced at both the mRNA and protein levels in the activated mutant cells. Meanwhile, a reduced level of activated caspase 9 was observed in the mutant cells. We conclude that reduced AICD in activated SAP -/-CD8 + T cells is associated with impaired p73 induction, indicating that the initiation of the mitochondrial apoptotic pathway might be impaired. Our data demonstrate an intrinsic defect in SAP -/-CD8 + T cells and shed light on the increased responsiveness of CD8 + T cells in SAP -/-mice. IntroductionX-linked lymphoproliferative syndrome (XLP), an abnormal immune response to EBV infection characterized by fatal infectious mononucleosis, dys-gammaglobulinemia and B cell lymphoma, is caused by mutations in the SH2D1A gene, which encodes signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) [1][2][3][4]. The adaptor SAP binds with high affinity to tyrosine motifs in the cytoplasmic domain of SLAM family immune receptors, including SLAM (CD150), CD244, CD229, SLAMF6, SLAMF7 and CD84, suggesting that SAP functions are important in modulating signals initiated by the SLAM family receptors [5][6][7][8]. It has been well established that SAP is an essential adaptor due to its capacity to recruit FynT to SLAM and p85 of PI3 K to 2B4, respectively [9,10]. SAP is expressed in activated T, NK and NKT cells, as well as in germinal center B cells [11,12], and is indispensable for normal NKT cell development, generation of a proper Th2 response and Ig class switching in humans and mice [13][14][15][16][17][18]. In XLP patients, both EBV-infected B cells and EBVspecific CTL hyper-proliferate, although the underlying mechanism is still controversial. Previous studies with SAP -/-mice, performed by several laboratories including ours, showed an increased antigen-specific CD8 + T cell population and IFN-c production after infection with lymphocytic choriomeningitis virus (LCMV), murine c-herpesvirus 68 (MHV-68) and Toxoplasma gondii, but impaired Th2 cell differentiation and decreased IgG production [15,19,20]. In addition, we demonstrate that SAP -/-mice confer greater cytotoxic activity and increased proliferation of CD8 + T cells compared to WT mice, strongly suggesting that SAP fine-tunes th...

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Section: Discussionmentioning

confidence: 65%

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

et al. 2007

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“…The process of ubiquitylation involves multiclasses of enzymes known as E1s, E2s, and E3s (12). Ubiquitin (Ub) 6 is activated first by an E1 (activating enzyme) to form a high-energy thiol-ester bond between Ub and the active site cysteine of E1. It is then transferred to an E2 (conjugating enzyme), again through a thiol-ester linkage.…”

mentioning

confidence: 99%

A Novel E3 Ubiquitin Ligase TRAC-1 Positively Regulates T Cell Activation

Zhao

Pardo

et al. 2005

The Journal of Immunology

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TRAC-1 (T cell RING (really interesting new gene) protein identified in activation screen) is a novel E3 ubiquitin ligase identified from a retroviral vector-based T cell surface activation marker screen. The C-terminal truncated TRAC-1 specifically inhibited anti-TCR-mediated CD69 up-regulation in Jurkat cells, a human T leukemic cell line. In this study, we show that TRAC-1 is a RING finger ubiquitin E3 ligase with highest expression in lymphoid tissues. Point mutations that disrupt the Zn2+-chelating ability of its amino-terminal RING finger domain abolished TRAC-1’s ligase activity and the dominant inhibitory effect of C-terminal truncated TRAC-1 on TCR stimulation. The results of in vitro biochemical studies indicate that TRAC-1 can stimulate the formation of both K48- and K63-linked polyubiquitin chains and therefore could potentially activate both degradative and regulatory ubiquitin-dependent pathways. Antisense oligonucleotides to TRAC-1 specifically reduced TRAC-1 mRNA levels in Jurkat and primary T cells and inhibited their activation in response to TCR cross-linking. Collectively, these results indicate that the E3 ubiquitin ligase TRAC-1 functions as a positive regulator of T cell activation.

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“…This phenotype inversely correlates with that of mice lacking JunB, the AP1 transcriptional factor responsible for gene regulation in Th2 cell differentiation [48]. Further studies suggest that Itch controls Th2 differentiation by binding and mediating JunB ubiquitin-dependent degradation [47]. However, as Itch is ubiquitously expressed, the contribution of other cellular and molecular Itch-dependent mechanisms to this complex phenotype cannot be excluded.…”

Section: Itchmentioning

confidence: 99%

“…This itching phenotype is characterized by a Th2 bias in T-cell development and a concomitant increase in the IL-2-dependent cytokines IL-4 and IL-5, as well as in serological levels of immunoglobulins IgG1 and IgE [47]. This phenotype inversely correlates with that of mice lacking JunB, the AP1 transcriptional factor responsible for gene regulation in Th2 cell differentiation [48].…”

Section: Itchmentioning

confidence: 99%

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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Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation

Cited by 310 publications

References 30 publications

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

A Novel E3 Ubiquitin Ligase TRAC-1 Positively Regulates T Cell Activation

E3 ubiquitin ligases in T‐cell tolerance

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Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation

Cited by 310 publications

References 30 publications

Increased proliferation of CD8+ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

Increased proliferation of CD8+ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

A Novel E3 Ubiquitin Ligase TRAC-1 Positively Regulates T Cell Activation

E3 ubiquitin ligases in T‐cell tolerance

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Product

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Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death