Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1.
Regulated apoptosis is essential for both the development and the subsequent maintenance of the immune system. 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. The antiapoptotic protein MCL-1 is an attractive candidate, as it is highly regulated, appears to enhance short-term survival and functions at an apical step in genotoxic deaths. However, Mcl-1 deficiency results in peri-implantation lethality. 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.
Opferman
Joseph T
JT
Howard Hughes Medical Institute, Dana Farber Cancer Institute, Department of Pathology and Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Letai
Anthony
A
Beard
Caroline
C
Sorcinelli
Mia D
MD
Ong
Christy C
CC
Korsmeyer
Stanley J
SJ
D000483:Alleles; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D001287:Attachment Sites, Microbiological / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D017353:Gene Deletion; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D018941:Antigens, CD19; D016207:Cytokines; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases