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* Division of Immunology and Rheumatology and
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants CA 65237-17, T32-AI07290-21, and U19-AI070352 and the Tom and Susan Ford Stanford Graduate Fellowship (to N.L.).
2 Current address: Department of Pediatrics, Division of Immunology and Rheumatology, University of Wisconsin, H4/474 Clinical Sciences Center, 600 Highland Avenue, Madison, WI 53792-4108.
3 Address correspondence and reprint requests to Dr. C. Garrison Fathman, Stanford University School of Medicine, Division of Immunology and Rheumatology, Center for Clinical Sciences Research Building, Room 2225, Stanford, CA 94305-5166. E-mail address: cfathman{at}stanford.edu
4 Abbreviations used in this paper: GRAIL, gene related to anergy in lymphocytes; CD40L, CD40 ligand; HA, hemagglutinin; PA, protease-associated domain; QPCR, real-time quantitative PCR; RING, really interesting new gene.
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