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Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1

Nature volume 426, pages 671–676 (2003)Cite this article

Abstract

Regulated apoptosis is essential for both the development and the subsequent maintenance of the immune system1,2. Interleukins, including IL-2, IL-4, IL-7 and IL-15, heavily influence lymphocyte survival during the vulnerable stages of VDJ rearrangement and later in ensuring cellular homeostasis, but the genes specifically responsible for the development and maintenance of lymphocytes have not been identified3,4,5,6,7,8. The antiapoptotic protein MCL-1 is an attractive candidate, as it is highly regulated9, appears to enhance short-term survival10 and functions at an apical step in genotoxic deaths11. However, Mcl-1 deficiency results in peri-implantation lethality12. Here we show that mice conditional for Mcl-1 display a profound reduction in B and T lymphocytes when MCL-1 is removed. Deletion of Mcl-1 during early lymphocyte differentiation increased apoptosis and arrested the development at pro-B-cell and double-negative T-cell stages. Induced deletion of Mcl-1 in peripheral B- and T-cell populations resulted in their rapid loss. Moreover, IL-7 both induced and required MCL-1 to mediate lymphocyte survival. Thus, MCL-1, which selectively inhibits the proapoptotic protein BIM, is essential both early in lymphoid development and later on in the maintenance of mature lymphocytes.

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Figure 1: Conditional deletion of Mcl-1 results in loss of peripheral lymphocytes.
Figure 2: Lck–Cre-mediated deletion of Mcl-1 blocks thymocyte development.
Figure 3: CD19–Cre-mediated deletion of Mcl-1 blocks B-cell development.
Figure 4: MCL-1 is required for mature lymphocyte survival.

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Acknowledgements

We thank G. Zambetti for providing the anti-MCL-1 antisera, S. Dowdy for the Tat–Cre, T. Oltersdorf for the GST fusion constructs, J. Fisher and S. Wade for animal husbandry, and E. Smith for editorial assistance. J.T.O. is supported by a postdoctoral fellowship from the Damon Runyon Cancer Research Foundation. This work is supported in part by a grant from the National Institutes of Health.

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  1. Howard Hughes Medical Institute, Dana Farber Cancer Institute, Department of Pathology and Medicine, Harvard Medical School, Massachusetts, 02115, Boston, USA

    Joseph T. Opferman, Anthony Letai, Caroline Beard, Mia D. Sorcinelli, Christy C. Ong & Stanley J. Korsmeyer

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  1. Joseph T. Opferman
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Correspondence to Stanley J. Korsmeyer.

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Opferman, J., Letai, A., Beard, C. et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426, 671–676 (2003). https://doi.org/10.1038/nature02067

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