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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3218-3225. Prepublished online as a Blood First Edition Paper on July 12, 2007; DOI 10.1182/blood-2007-01-070359. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-01-070359v1 110/9/3218    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 Maraver, A. Articles by Lafaille, J. J. Search for Related Content PubMed PubMed Citation Articles by Maraver, A. Articles by Lafaille, J. J. Related Collections Apoptosis Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Effect of presenilins in the apoptosis of thymocytes and homeostasis of CD8+ T cells Antonio Maraver1,2, Carlos E. Tadokoro1, Michelle L. Badura1, Jie Shen3, Manuel Serrano2, and Juan J. Lafaille1,4 1 Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York; 2 Molecular and Oncology Program, Spanish National Cancer Center (CNIO), Madrid, Spain; 3 Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; 4 Department of Pathology, New York University School of Medicine, New York Many studies have positioned Notch signaling at various critical junctions during T-cell development. There is, however, debate regarding the role of Notch in the CD4 versus CD8 lineage commitment. Because there are 4 Notch receptors and RBP-J–independent Notch signaling has been reported, we decided to eliminate -secretase activity once its activity is required for all forms of Notch signaling. T-cell–specific elimination of -secretase was carried out by crossing presenilin-1 (PS1) floxed mice with CD4-Cre mice and PS2 KO mice, generating PS KO mice. Thymic CD4+CD8+ double-positive (DP) cells from these mice were strikingly resistant to apoptosis by anti-CD3 treatment in vivo and expressed more Bcl-XL than control thymocytes, and deletion of only one allele of Bcl-XL gene restored wild-type levels of sensitivity to apoptosis. In addition, these PS KO animals displayed a significant decrease in the number of CD8+ T cells in the periphery, and these cells had higher level of phosphorylated p38 than cells from control littermates. Our results show that ablation of presenilins results in deficiency of CD8 cells in the periphery and a dramatic change in the physiology of thymocytes, bringing to our attention the potential side effects of presenilin inhibitors in ongoing clinical trials. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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