Submitted January 26, 2007
Accepted July 9, 2007
Effect of Presenilins in the apoptosis of thymocytes and homeostasis of CD8+ T cells
Antonio Maraver, Carlos E Tadokoro, Michelle L Badura, Jie Shen, Manuel Serrano, and Juan J Lafaille*
Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, United States
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
Molecular and Oncology Program, Spanish National Cancer Center (CNIO), Madrid, Spain
Department of Pathology, New York University School of Medicine, New York, NY, United States
* Corresponding author; email: lafaille{at}saturn.med.nyu.edu.
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. Since there are four 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, 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 presenilins inhibitors in ongoing clinical trials.
