Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

J. Biol. Chem. 282 (13): 9696-9702

© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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{ddagger}, Jill Schartner{ddagger}, Jack Lin§, Amanda Timmel{ddagger}, Martha Jennens-Clough{ddagger}, C. Garrison Fathman§, , and Christine M. Seroogy{ddagger}1

{ddagger}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

Abstract: 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. Revision received 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.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Tissue-specific disallowance of housekeeping genes: The other face of cell differentiation.
L. Thorrez, I. Laudadio, K. Van Deun, R. Quintens, N. Hendrickx, M. Granvik, K. Lemaire, A. Schraenen, L. Van Lommel, S. Lehnert, et al. (2011)
Genome Res. 21, 95-105
   Abstract »    Full Text »    PDF »
Anergic CD4+ T Cells Form Mature Immunological Synapses with Enhanced Accumulation of c-Cbl and Cbl-b.
M. Doherty, D. G. Osborne, D. L. Browning, D. C. Parker, and S. A. Wetzel (2010)
J. Immunol. 184, 3598-3608
   Abstract »    Full Text »    PDF »
Gene Related to Anergy in Lymphocytes (GRAIL) Expression in CD4+ T Cells Impairs Actin Cytoskeletal Organization during T Cell/Antigen-presenting Cell Interactions.
J. M. Schartner, W. T. Simonson, S. A. Wernimont, L. M. Nettenstrom, A. Huttenlocher, and C. M. Seroogy (2009)
J. Biol. Chem. 284, 34674-34681
   Abstract »    Full Text »    PDF »
E3 ubiquitin ligase GRAIL controls primary T cell activation and oral tolerance.
M. A. Kriegel, C. Rathinam, and R. A. Flavell (2009)
PNAS 106, 16770-16775
   Abstract »    Full Text »    PDF »
Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance.
N. Soto-Nieves, I. Puga, B. T. Abe, S. Bandyopadhyay, I. Baine, A. Rao, and F. Macian (2009)
J. Exp. Med. 206, 867-876
   Abstract »    Full Text »    PDF »
CD69+CD4+CD25- T Cells, a New Subset of Regulatory T Cells, Suppress T Cell Proliferation through Membrane-Bound TGF-{beta}1.
Y. Han, Q. Guo, M. Zhang, Z. Chen, and X. Cao (2009)
J. Immunol. 182, 111-120
   Abstract »    Full Text »    PDF »
Upregulation of GRAIL is associated with remission of ulcerative colitis.
S. Egawa, H. Iijima, S. Shinzaki, S. Nakajima, J. Wang, J. Kondo, S. Ishii, T. Yoshio, T. Irie, T. Nishida, et al. (2008)
Am J Physiol Gastrointest Liver Physiol 295, G163-G169
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882