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Blood, 7 May 2009, Vol. 113, No. 19, pp. 4575-4585. Prepublished online as a Blood First Edition Paper on February 9, 2009; DOI 10.1182/blood-2008-10-185223. This Article Full Text Full Text (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2008-10-185223v1 113/19/4575    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Parish, I. A. Articles by Heath, W. R. Search for Related Content PubMed PubMed Citation Articles by Parish, I. A. Articles by Heath, W. R. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY The molecular signature of CD8+ T cells undergoing deletional tolerance Ian A. Parish13, Sudha Rao4, Gordon K. Smyth1, Torsten Juelich4, Gareth S. Denyer5, Gayle M. Davey1,6, Andreas Strasser1, and William R. Heath1,6 1 Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; 2 Department of Medical Biology, University of Melbourne, Parkville, Australia; 3 Immunobiology Department, Yale School of Medicine, New Haven, CT; 4 Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Acton, Australia; 5 School of Molecular and Microbial Biosciences, University of Sydney, Sydney, Australia; and 6 Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia Peripheral tolerance induction is critical for the maintenance of self-tolerance and can be mediated by immunoregulatory T cells or by direct induction of T-cell anergy or deletion. Although the molecular processes underlying anergy have been extensively studied, little is known about the molecular basis for peripheral T-cell deletion. Here, we determined the gene expression signature of peripheral CD8+ T cells undergoing deletional tolerance, relative to those undergoing immunogenic priming or lymphopenia-induced proliferation. From these data, we report the first detailed molecular signature of cells undergoing deletion. Consistent with defective cytolysis, these cells exhibited deficiencies in granzyme up-regulation. Furthermore, they showed antigen-driven Bcl-2 down-regulation and early up-regulation of the proapoptotic protein Bim, consistent with the requirement of this BH3-only protein for peripheral T-cell deletion. Bim up-regulation was paralleled by defective interleukin-7 receptor (IL-7R) chain reexpression, suggesting that Bim-dependent death may be triggered by loss of IL-7/IL-7R signaling. Finally, we observed parallels in molecular signatures between deletion and anergy, suggesting that these tolerance pathways may not be as molecularly distinct as previously surmised. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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