c-Myb Regulates the Survival of CD4+CD8+Double Positive Thymocytes 461 views

The peripheral T cell repertoire is selected during the CD4+CD8+ double positive (DP) stage of T cell development for optimized pathogen recognition while maintaining self-tolerance. <i>Bcl2l1</i> encodes the survival factor Bcl-xL, which is specifically upregulated in DP thymocytes to prolong the window of time available for <i>Tcra</i> rearrangements and the generation of a diverse T cell repertoire. However, despite the importance of <i>Bcl2l1</i> during T cell development, the regulation of its expression remains poorly understood. The <i>Myb</i> proto-oncogene encodes an essential transcription factor that plays critical roles during several stages of T cell development including DN to DP thymocyte development, DP thymocyte survival and the development of CD4SP thymocytes. Work in this thesis demonstrates that <i>Myb</i> mRNA expression is specifically upregulated in the small, preselection DP stage during T cell development. Using a conditional deletion model in which deletion at the <i>Myb</i> locus takes place in DP thymocytes, we demonstrate that <i>Myb</i> deficient DP thymocytes undergo premature apoptosis, resulting in a limited <i>Tcra</i> repertoire biased towards 5' Jα segment usage. Premature apoptosis occurs in an αβ-TCR independent manner and is a consequence of decreased Bcl-xL expression. Reintroduction of c-Myb restores both Bcl-xL expression and the small pre-selection DP compartment and forced Bcl-xL expression is able to rescue survival. However, prolonged survival alone cannot restore the CD4SP compartment in Myb deficient mice, suggesting that c-Myb is able to enhance CD4SP lineage representation independent of its ability to prolong DP thymocyte survival. Work in this thesis makes clear that c-Myb promotes <i>Bcl2l1</i> transcription </i>in vivo</i> via a novel genetic pathway independent of the expression of TCF-1 or ROR<i>γt</i>, two transcription factors previously reported to induce Bcl-xL expression during T cell development. In conclusion, this thesis work establishes Bcl-xL as a novel mediator of c-Myb activity and sheds new light on the regulation of cell survival during a critical stage of normal T cell development. Note: Abstract extracted from PDF text

PHD (Doctor of Philosophy)

English

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2009-12-01