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

Correspondence to: Stanley J. Korsmeyer¹ Email: stanley_korsmeyer@dfci.harvard.edu

Abstract

Regulated apoptosis is essential for both the development and the subsequent maintenance of the immune system^{1, 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 identified^{3, 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.