The Journal of Experimental Medicine
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Published online 29 December 2003 doi:10.1084/jem.20031588
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 1, 69-80
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Essential Role of Survivin, an Inhibitor of Apoptosis Protein, in T Cell Development, Maturation, and Homeostasis

Zheng Xing1, Edward M. Conway2, Chulho Kang1 and Astar Winoto1

1 Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720
2 Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, B-3000 Leuven, Belgium

Address correspondence to Astar Winoto, Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California at Berkeley, 469 LSA, Berkeley, CA 94720. Phone: (510) 642-0217; Fax: (510) 642-0468; email: winoto{at}uclink4.berkeley.edu

Survivin is an inhibitor of apoptosis protein that also functions during mitosis. It is expressed in all common tumors and tissues with proliferating cells, including thymus. To examine its role in apoptosis and proliferation, we generated two T cell–specific survivin-deficient mouse lines with deletion occurring at different developmental stages. Analysis of early deleting survivin mice showed arrest at the pre–T cell receptor proliferating checkpoint. Loss of survivin at a later stage resulted in normal thymic development, but peripheral T cells were immature and significantly reduced in number. In contrast to in vitro studies, loss of survivin does not lead to increased apoptosis. However, newborn thymocyte homeostatic and mitogen-induced proliferation of survivin-deficient T cells were greatly impaired. These data suggest that survivin is not essential for T cell apoptosis but is crucial for T cell maturation and proliferation, and survivin-mediated homeostatic expansion is an important physiological process of T cell development.

Key Words: proliferation • apoptosis • T cell development • survivin • IAP

Abbreviations used in this paper: 7-AAD, 7-amino actinomycin D; BrdU, 5-bromo-2-deoxyuridine; CFSE, carboxy fluorescein diacetate succinimidyl ester; DN, double negative; DP, double positive; ES, embryonic stem; HSA, heat-stable antigen; IAP, inhibitor of apoptosis protein; SP, single positive.


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