Journal
JOURNAL OF IMMUNOLOGY
Volume 184, Issue 6, Pages 2793-2804Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0902846
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Funding
- National Institutes of Health [CA85842]
- Robert R. Wagner Fellowship
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Mechanisms that regulate the lifespan of CD4(+)CD8(+) double-positive (DP) thymocytes help shape the peripheral T cell repertoire. However, the molecular mechanisms controlling DP thymocyte survival remain poorly understood. The Myb proto-oncogene encodes a transcription factor required during multiple stages of T cell development. We demonstrate that Myb mRNA expression is upregulated as thymocytes differentiate from the double-negative into the metabolically quiescent, small, preselection DP stage during T cell development. Using a conditional deletion mouse model, we demonstrate that Myb-deficient DP thymocytes undergo premature apoptosis, resulting in a limited Tcr alpha repertoire biased toward 5' J alpha segment usage. Premature apoptosis occurs specifically in the small preselection DP compartment in an alpha beta TCR-indepenclent manner and is a consequence of decreased Bcl-xL expression. Forced Bcl-xL expression is able to rescue survival, and reintroduction of c-Myb restores both Bcl-xL expression and the small preselection DP compartment. We further demonstrate that c-Myb promotes transcription at the Bcl2l1 locus via a genetic pathway that is independent of the expression of T cell-specific factor-1 or ROR gamma t, two transcription factors that induce Bcl-xL expression in T cell development. Thus, Bcl-xL is a novel mediator of c-Myb activity during normal T cell development. The Journal of Immunology, 2010, 184: 2793-2804.
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