The Journal of Experimental Medicine
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Published online 25 October 2004 doi:10.1084/jem.20041328
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 9, 1189-1195
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Brief Definitive Report

 Loss of Bim Increases T Cell Production and Function in Interleukin 7 Receptor–deficient Mice

Marc Pellegrini, Philippe Bouillet, Mikara Robati, Gabrielle T. Belz, Gayle M. Davey, and Andreas Strasser

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia

Address correspondence to Andreas Strasser, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. Phone: 61-3-9345-2624; Fax: 61-3-9347-0852; email: strasser{at}wehi.edu.au

Interleukin (IL)-7 receptor (R) signaling is essential for T and B lymphopoiesis by promoting proliferation, differentiation, and survival of cells. Mice lacking either IL-7 or the IL-7R{alpha} chain have abnormally low numbers of immature as well as mature T and B lymphocytes. Transgenic expression of the apoptosis inhibitor Bcl-2 rescues T cell development and function in IL-7R{alpha}–deficient mice, indicating that activation of a proapoptotic Bcl-2 family member causes death of immature and mature T cells. BH3-only proteins such as Bim, which are distant proapoptotic members of the Bcl-2 family, are essential initiators of programmed cell death and stress-induced apoptosis. We generated Bim/IL-7R{alpha} double deficient mice and found that loss of Bim significantly increased thymocyte numbers, restored near normal numbers of mature T cells in the blood and spleen, and enhanced cytotoxic T cell responses to virus infection in IL-7R{alpha}–/– mice. These results indicate that Bim cooperates with other proapoptotic proteins in the death of IL-7–deprived T cell progenitors in vivo, but is the major inducer of this pathway to apoptosis in mature T cells. This indicates that pharmacological inhibition of Bim function might be useful for boosting immune responses in immunodeficient patients.

Key Words: apoptosis • Bim • Bcl-2 • IL-7 • T cells

M. Pellegrini and P. Bouillet contributed equally to this work.

M. Pellegrini's present address is Dept. of Immunology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1AB, Canada.


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