Elevated Mcl-1 inhibits thymocyte apoptosis and alters thymic selection

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 deter...

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Bibliographic Details
Published in:Cell death and differentiation 2012-12, Vol.19 (12), p.1962-1971
Main Authors: Campbell, K J, Gray, D H D, Anstee, N, Strasser, A, Cory, S
Format: Article
Language:English
Subjects:
631/250/1619/554
631/80/82/23
Animals
Antigens
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Cell death
Cytotoxicity
Female
Life Sciences
Lymphocytes
Male
Medical research
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myeloid Cell Leukemia Sequence 1 Protein
Original Paper
Proteins
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Receptor-CD3 Complex, Antigen, T-Cell - immunology
Receptor-CD3 Complex, Antigen, T-Cell - metabolism
Stem Cells
Thymocytes - metabolism
Thymus gland
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Summary: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.
ISSN:1350-9047
1476-5403
DOI:10.1038/cdd.2012.84