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

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. Bcl2l1 encodes the survival factor Bcl-xL, which is specifically upregulated in DP thymocytes to prolong the window of time available for Tcra rearrangements and the generation of a diverse T cell repertoire. However, despite the importance of Bcl2l1 during T cell development, the regulation of its expression remains poorly understood. The Myb 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 Myb 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 Myb locus takes place in DP thymocytes, we demonstrate that Myb deficient DP thymocytes undergo premature apoptosis, resulting in a limited Tcra 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 Bcl2l1 transcription in vivo via a novel genetic pathway independent of the expression of TCF-1 or RORγt, 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.

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