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Cutting Edge: The Transmembrane E3 Ligase GRAIL Ubiquitinates the Costimulatory Molecule CD40 Ligand during the Induction of T Cell Anergy

Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
The Journal of Immunology (Impact Factor: 5.36). 08/2008; 181(3):1622-6. DOI: 10.4049/jimmunol.181.3.1622
Source: PubMed

ABSTRACT Activation of naive T lymphocytes is regulated through a series of discrete checkpoints that maintain unresponsiveness to self. During this multistep process, costimulatory interactions act as inducible signals that allow APCs to selectively mobilize T cells against foreign Ags. In this study, we provide evidence that the anergy-associated E3 ubiquitin ligase GRAIL (gene related to anergy in lymphocytes) regulates expression of the costimulatory molecule CD40L on CD4 T cells. Using its luminal protease-associated domain, GRAIL binds to the luminal/extracellular portion of CD40L and facilitates transfer of ubiquitin molecules from the intracellular GRAIL RING (really interesting new gene) finger to the small cytosolic portion of CD40L. Down-regulation of CD40L occurred following ectopic expression of GRAIL in naive T cells from CD40(-/-) mice, and expression of GRAIL in bone marrow chimeric mice was associated with diminished lymphoid follicle formation. These data provide a model for intrinsic T cell regulation of costimulatory molecules and a molecular framework for the initiation of clonal T cell anergy.

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    • "GRAIL promotes CD3 ubiquitination and consequently, GRAIL-deficient T cells fail to regulate TCR expression in response to TCR stimulation and have an enhanced activation of NFATc1, while T cells expressing GRAIL present an enhanced TCR downregulation (107). It has been suggested that GRAIL is also responsible for the decrease cell surface expression of CD40L that occurs following anergy induction of CD4+ T cells (121). Furthermore, similarly to CD40L−/− mice, GRAIL overexpression results in reduced lymphoid follicle formation. "
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    ABSTRACT: Autoimmune diseases are characterized by the production of antibodies against self-antigens and generally arise from a failure of central or peripheral tolerance. However, these diseases may develop when newly appearing antigens are not recognized as self by the immune system. The mechanism by which some antigens are "invisible" to the immune system is not completely understood. Apoptotic and complement system defects or autophagy imbalance can generate this antigenic autoreactivity. Under particular circumstances, cellular debris containing autoreactive antigens can be recognized by innate immune receptors or other sensors and can eventually lead to autoimmunity. Ubiquitination may be one of the mechanisms protecting autoreactive antigens from the immune system that, if disrupted, can lead to autoimmunity. Ubiquitination is an essential post-translational modification used by cells to target proteins for degradation or to regulate other intracellular processes. The level of ubiquitination is regulated during T cell tolerance and apoptosis and E3 ligases have emerged as a crucial signaling pathway for the regulation of T cell tolerance toward self-antigens. I propose here that an unrecognized role of ubiquitin and ubiquitin-like proteins could be to render intracellular or foreign antigens (present in cellular debris resulting from apoptosis, complement system, or autophagy defects) invisible to the immune system in order to prevent the development of autoimmunity.
    Frontiers in Immunology 06/2014; 5:262. DOI:10.3389/fimmu.2014.00262
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    • "Another possibility is post-translational modification of pCD40L. It is reported that GRAIL (gene related to anergy in lymphocytes) directly downregulates CD40L through its E3 ubiquitin ligase activity [65], although this finding is controversial since GRAIL-deficient mice from two different groups did not show any evidence of CD40L overexpression [66], [67]. Investigation of the cause(s) of the lack of pCD40L in Treg cells could shed light on how effector CD4+ T cells acquire and regulate pCD40L. "
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    ABSTRACT: CD40L is essential for the development of adaptive immune responses. It is generally thought that CD40L expression in CD4(+) T cells is regulated transcriptionally and made from new mRNA following antigen recognition. However, imaging studies show that the majority of cognate interactions between effector CD4(+) T cells and APCs in vivo are too short to allow de novo CD40L synthesis. We previously showed that Th1 effector and memory cells store preformed CD40L (pCD40L) in lysosomal compartments and mobilize it onto the plasma membrane immediately after antigenic stimulation, suggesting that primed CD4(+) T cells may use pCD40L to activate APCs during brief encounters. Indeed, our recent study showed that pCD40L is sufficient to mediate selective activation of cognate B cells and trigger DC activation in vitro. In this study, we show that pCD40L is present in Th1 and follicular helper T cells developed during infection with lymphocytic choriomeningitis virus, Th2 cells in the airway of asthmatic mice, and Th17 cells from the CNS of animals with experimental autoimmune encephalitis (EAE). pCD40L is nearly absent in both natural and induced Treg cells, even in the presence of intense inflammation such as occurs in EAE. We also found pCD40L expression in CD4 single positive thymocytes and invariant NKT cells. Together, these results suggest that pCD40L may function in T cell development as well as an unexpectedly broad spectrum of innate and adaptive immune responses, while its expression in Treg cells is repressed to avoid compromising their suppressive activity.
    PLoS ONE 02/2012; 7(2):e31296. DOI:10.1371/journal.pone.0031296 · 3.23 Impact Factor
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    • "GRAIL thus may have more restricted specificity than cbl-b or Itch. Recently, Lineberry et al. proposed CD40L as another potential target for GRAIL (Lineberry et al., 2008). However, we did not detect an increase in CD40L expression in Rnf128 −/− cells in comparison to WT cells (data not shown). "
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    ABSTRACT: T cell activation is tightly regulated to avoid autoimmunity. Gene related to anergy in lymphocytes (GRAIL, encoded by Rnf128) is an E3 ubiquitin ligase associated with T cell tolerance. Here, we generated and analyzed GRAIL-deficient mice and found they were resistant to immune tolerance induction and exhibited greater susceptibility to autoimmune diseases than wild-type mice. GRAIL-deficient naive T cells, after activation, exhibited increased proliferation and cytokine expression than controls and did not depend on costimulation for effector generation. Moreover, GRAIL-deficient regulatory T (Treg) cells displayed reduced suppressive function, associated with increased Th17 cell-related gene expression. GRAIL-deficient naive and Treg cells were less efficient in downregulating T cell receptor (TCR)-CD3 expression after activation and exhibited increased NFATc1 transcription factor expression; GRAIL expression promoted CD3 ubiquitinylation. Our results indicate that GRAIL, by mediating TCR-CD3 degradation, regulates naive T cell tolerance induction and Treg cell function.
    Immunity 05/2010; 32(5):670-80. DOI:10.1016/j.immuni.2010.05.002 · 19.75 Impact Factor
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