Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice.
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-7Ralpha 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-7Ralpha-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-7Ralpha 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-7Ralpha-/- 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.
Pellegrini
Marc
M
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Bouillet
Philippe
P
Robati
Mikara
M
Belz
Gabrielle T
GT
Davey
Gayle M
GM
Strasser
Andreas
A
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D005455:Fluorescent Antibody Technique; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008817:Mice, Mutant Strains; D011518:Proto-Oncogene Proteins / Q000172:deficiency*; D020395:Receptors, Interleukin-7 / Q000172:deficiency*; D018139:Simplexvirus / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000821:virology
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020395:Receptors, Interleukin-7