c-Myb promotes the survival of CD4+CD8+ double-positive thymocytes through upregulation of Bcl-xL.
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 Tcralpha repertoire biased toward 5' Jalpha segment usage. Premature apoptosis occurs specifically in the small preselection DP compartment in an alphabetaTCR-independent 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 RORgammat, 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.
Department of Microbiology, Beirne B Carter Center for Immunology Research, University of Virginia Health System, Charlottesville, VA 22908, USA.
Joan
J
Yuan
Rowena B
RB
Crittenden
Timothy P
TP
Bender
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000235:genetics; D016827:CD8 Antigens / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D018920:Coculture Techniques; D019426:Integrases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020598:Proto-Oncogene Proteins c-myb / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
C494812:Bcl2l1 protein, mouse; D015704:CD4 Antigens; D016827:CD8 Antigens; D020598:Proto-Oncogene Proteins c-myb; D051020:bcl-X Protein; C045073:Cre recombinase; D019426:Integrases