Abstract
FoxM1 is a forkhead box transcription factor and a known master regulator required for different phases of the cell cycle. In cell lines, FoxM1 deficient cells exhibit delayed S phase entry, aneuploidy, polyploidy and can't complete mitosis. In vivo, FoxM1 is expressed mostly in proliferating cells but is surprisingly also found in non-proliferating CD4+CD8+ double positive thymocytes. Here, we addressed the role of FoxM1 in T cell development by generating and analyzing two different lines of T-cell specific FoxM1 deficient mice. As expected, FoxM1 is required for proliferation of early thymocytes and activated mature T cells. Defective expression of many cell cycle proteins was detected, including cyclin A, cyclin B1, cdc2, cdk2, p27 and the Rb family members p107 and p130 but surprisingly not survivin. Unexpectedly, loss of FoxM1 only affects a few cell cycle proteins in CD4+CD8+ thymocytes and has little effect on their sensitivity to apoptosis and the subsequent steps of T cell differentiation. Thus, regulation of cell cycle genes by FoxM1 is stage- and context-dependent.
Highlights
Proliferation and apoptosis are integral parts of T cell development
Deletion of FoxM1 is expected to occur before the preTCR mediated proliferation that takes place between DN3 (CD42CD82 CD252CD44+) and DN4 (CD42CD82 CD252 CD442) T cells
We concluded that the absence of FoxM1 early during T cell development only modestly affects the transition of differentiation of CD42CD82 (DN) to DP T cells and has no effect in later stages of T cell differentiation
Summary
Proliferation and apoptosis are integral parts of T cell development. Early thymocytes die if their T-cell receptor (TCR) b genes do not rearrange successfully to produce a functional protein. Formation of a cell surface pre-TCR complex, consisting of TCRb/pTa/CD3 will result in proliferation and differentiation of CD42CD82 (DN) thymocytes into CD4+ CD8+(DP) thymocytes [1,2,3,4,5]. A small fraction of DP cells with the appropriate TCRab/CD3 complex can differentiate into CD4+CD82 or CD42CD8+ SP thymocytes. These cells migrate to the peripheral immune organs, spleen and lymph nodes. In life, when these organs are relatively empty, homeostatic proliferation of SP cells takes place to fill the empty niches. This homeostatic proliferation ceases in adult mice. Mature T cells exist in the G0 state of the cell cycle and proliferate only when stimulated through their TCR complex
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