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

• Published in: Nature (London) 2003-12, Vol.426 (6967), p.671-676
• Main Authors: Opferman, Joseph T., Letai, Anthony, Beard, Caroline, Sorcinelli, Mia D., Ong, Christy C., Korsmeyer, Stanley J.
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Antigens, CD19 - genetics; Apoptosis - drug effects; Attachment Sites, Microbiological - genetics; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; BIM protein; Biological and medical sciences; Cell Differentiation - drug effects; Cell Lineage; Cell Survival - drug effects; Cells, Cultured; Cytokines - pharmacology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Deletion; Humanities and Social Sciences; Immune system; Immunobiology; Immunology; Integrases - genetics; Integrases - metabolism; letter; Lymphatic system; Lymphocytes; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; Mcl-1 gene; MCL-1 protein; Mice; multidisciplinary; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Organ Specificity; Proteins; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Spleen - cytology; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Thymus Gland - cytology; Viral Proteins - genetics; Viral Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02067

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 regulated 9 , appears to enhance short-term survival 10 and functions at an apical step in genotoxic deaths 11 . However, Mcl-1 deficiency results in peri-implantation lethality 12 . 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.