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J. Biol. Chem., Vol. 282, Issue 13, 9696-9702, March 30, 2007

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GRAIL Is Up-regulated in CD4⁺ CD25⁺ T Regulatory Cells and Is Sufficient for Conversion of T Cells to a Regulatory Phenotype^*

Debra A. MacKenzie, Jill Schartner, Jack Lin, Amanda Timmel, Martha Jennens-Clough, C. Garrison Fathman, and Christine M. Seroogy¹

From the Department of Pediatrics, Division of Allergy/Immunology/Rheumatology, University of Wisconsin, Madison, Wisconsin 53792 and the Department of Medicine, Division of Immunology/Rheumatology, Stanford University, Stanford, California 94305

GRAIL (gene related to anergy in lymphocytes) is an ubiquitin-protein isopeptide ligase (E3) ubiquitin ligase necessary for the induction of CD4⁺ T cell anergy in vivo. We have extended our previous studies to characterize the expression pattern of GRAIL in other murine CD4⁺ T cell types with a described anergic phenotype. These studies revealed that GRAIL expression is increased in naturally occurring (thymically derived) CD4⁺ CD25⁺ T regulatory cells (mRNA levels 10-fold higher than naive CD25^– T cells). Further investigation demonstrated that CD25⁺ Foxp3⁺ antigen-specific T cells were induced after a "tolerizing-administration" of antigen and that GRAIL expression correlated with the CD25⁺ Foxp3⁺ antigen-specific subset. Lastly, using retroviral transduction, we demonstrated that forced expression of GRAIL in a T cell line was sufficient for conversion of these cells to a regulatory phenotype in the absence of detectable Foxp3. These data demonstrate that GRAIL is differentially expressed in naturally occurring and peripherally induced CD25⁺ T regulatory cells and that the expression of GRAIL is linked to their functional regulatory activity.

Received for publication, May 2, 2006 , and in revised form, January 26, 2007.

^* 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 To whom correspondence should be addressed: Dept. of Pediatrics, Division of Immunology and Rheumatology H4/474 CSC, 600 Highland Ave., University of Wisconsin, Madison, WI 53792-4108. Tel.: 608-263-2652; Fax: 608-263-0722; E-mail: cmseroogy{at}wisc.edu.

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