Elevated Mcl-1 inhibits thymocyte apoptosis and alters thymic selection

Campbell, KJ; Gray, DHD; Anstee, N; Strasser, A; Cory, S

Author(s): Campbell, KJ; Gray, DHD; Anstee, N; Strasser, A; Cory, S;
Details: Publication Year 2012-12,Volume 19,Issue #12,Page 1962-1971
Journal Title: CELL DEATH AND DIFFERENTIATION
Publication Type: Journal Article
Abstract: T cells developing in the thymus undergo rigorous positive and negative selection to ensure that those exported to peripheral lymphoid organs bear T-cell receptors (TCRs) capable of reacting with foreign antigens but tolerant of self. At each checkpoint, whether a thymocyte survives or dies is determined by antiapoptotic and proapoptotic Bcl-2 family members. We used Mcl-1 transgenic (tg) mice to investigate the impact of elevated expression of antiapoptotic Mcl-1 on thymocyte apoptosis and selection, making a side-by-side comparison with thymocytes from BCL-2tg mice. Mcl-1 was as effective as Bcl-2 at protecting thymocytes against spontaneous cell death, diverse cytotoxic insults and TCR-CD3 stimulation-driven apoptosis. In three different TCR tg models, Mcl-1 markedly enhanced positive selection of thymocytes, as did Bcl-2. In H-Y TCR tg mice, elevated Mcl-1 and Bcl-2 were equally effective at inhibiting deletion of autoreactive thymocytes. However, in the OT-1tg model where deletion is mediated by a peripheral antigen whose expression is regulated by Aire, Mcl-1 was less effective than Bcl-2. Thus, the capacity of Mcl-1 overexpression to inhibit apoptosis triggered by TCR stimulation apparently depends on the thymocyte subset subject to deletion, presumably due to differences in the profiles of proapoptotic Bcl-2 family members mediating the deletion. Cell Death and Differentiation (2012) 19, 1962-1971; doi:10.1038/cdd.2012.84; published online 29 June 2012
Publisher: NATURE PUBLISHING GROUP
Research Division(s): Molecular Genetics Of Cancer
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504710/
Publisher's Version: https://doi.org/10.1038/cdd.2012.84

Creation Date: 2012-12-01 12:00:00