The Journal of Experimental Medicine
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Published 22 February 2005. doi:10.1084/jem.20041924
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 4, 603-614
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ARTICLE

 The BCL2A1 gene as a pre–T cell receptor–induced regulator of thymocyte survival

Malay Mandal1, Christine Borowski2, Teresa Palomero3, Adolfo A. Ferrando3, Philipp Oberdoerffer5, Fanyong Meng1, Antonio Ruiz-Vela4, Maria Ciofani6, Juan-Carlos Zuniga-Pflucker6, Isabella Screpanti7, A. Thomas Look3, Stanley J. Korsmeyer4, Klaus Rajewsky5, Harald von Boehmer2, and Iannis Aifantis1

1 Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL 60637
2 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute
3 Department of Pediatric Oncology, Dana-Farber Cancer Institute
4 Howard Hughes Medical Institute, Dana-Farber Cancer Institute
5 Center for Blood Research, Harvard Medical School, Boston, MA 02115
6 Department of Immunology, University of Toronto, Sunnybrook and Women's College Health Sciences Center, Toronto M4N 3M5, Canada
7 Department of Experimental Medicine and Pathology, University La Sapienza, 00185 Rome, Italy

CORRESPONDENCE Iannis Aifantis: iaifanti{at}medicine.bsd.uchicago.edu

The pre–T cell receptor (TCR) is expressed early during T cell development and imposes a tight selection for differentiating T cell progenitors. Pre-TCR–expressing cells are selected to survive and differentiate further, whereas pre-TCR– cells are "negatively" selected to die. The mechanisms of pre-TCR–mediated survival are poorly understood. Here, we describe the induction of the antiapoptotic gene BCL2A1 (A1) as a potential mechanism regulating inhibition of pre–T cell death. We characterize in detail the signaling pathway involved in A1 induction and show that A1 expression can induce pre–T cell survival by inhibiting activation of caspase-3. Moreover, we show that in vitro "knockdown" of A1 expression can compromise survival even in the presence of a functional pre-TCR. Finally, we suggest that pre-TCR–induced A1 overexpression can contribute to T cell leukemia in both mice and humans.

Abbreviations used: cPKC, conventional protein kinase C; DAG, diacylglycerol; DN, double negative; Iono, ionomycin; DP, double positive; nPKC, novel protein kinase C; PKC, protein kinase C; PLC{gamma}, phospholipase C{gamma}; pT{alpha}, pre-TCR{alpha}; siRNA, short interfering RNA; T-ALL, T cell acute leukemia.

M. Mandal and C. Borowski contributed equally to this work.


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