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Naive CD4 T Cell Proliferation Is Controlled by Mammalian Target of Rapamycin Regulation of GRAIL Expression¹

Jack T. Lin^*, Neil B. Lineberry^*, Michael G. Kattah^*, Leon L. Su^*, Paul J. Utz^*, C. Garrison Fathman^2,* and Linda Wu

^* Stanford University School of Medicine, Department of Medicine, Division of Immunology and Rheumatology, Stanford, CA 94305; and Medarex, Milpitas, CA 95035

In this study, we demonstrate that the E3 ubiquitin ligase gene related to anergy in lymphocytes (GRAIL) is expressed in quiescent naive mouse and human CD4 T cells and has a functional role in inhibiting naive T cell proliferation. Following TCR engagement, CD28 costimulation results in the expression of IL-2 whose signaling through its receptor activates the Akt-mammalian target of rapamycin (mTOR) pathway. Activation of mTOR allows selective mRNA translation, including the epistatic regulator of GRAIL, Otubain-1 (Otub1), whose expression results in the degradation of GRAIL and allows T cell proliferation. The activation of mTOR appears to be the critical component of IL-2R signaling regulating GRAIL expression. CTLA4-Ig treatment blocks CD28 costimulation and resultant IL-2 expression, whereas rapamycin and anti-IL-2 treatment block mTOR activation downstream of IL-2R signaling. Thus, all three of these biotherapeutics inhibit mTOR-dependent translation of mRNA transcripts, resulting in blockade of Otub1 expression, maintenance of GRAIL, and inhibition of CD4 T cell proliferation. These observations provide a mechanistic pathway sequentially linking CD28 costimulation, IL-2R signaling, and mTOR activation as important requirements for naive CD4 T cell proliferation through the regulation of Otub1 and GRAIL expression. Our findings also extend the role of GRAIL beyond anergy induction and maintenance, suggesting that endogenous GRAIL regulates general cell cycle and proliferation of primary naive CD4 T cells.

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 grants from the National Institutes of Health Grants CA065237 (to C.G.F.) and AI07290 (to J.T.L.).

² Address correspondence and reprint requests to Dr. C. Garrison Fathman, Stanford University School of Medicine, 269 Campus Drive West, CCSR Building Room 2225, Department of Medicine, Division of Immunology and Rheumatology, Stanford, CA 94305. E-mail address: cfathman{at}stanford.edu

³ Abbreviations used in this paper: GRAIL, gene related to anergy in lymphocyte; mTOR, mammalian target of rapamycin; Otub1, Otubain-1; pOVA, peptide OVA_323–339.

⁴ The online version of this article contains supplemental material.

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The JI 2009 182: 5887-5888. [Full Text]