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Impact of KLF2 expression on T cell genetic program

ABSTRACT: On triggering of the T cell receptor CD8 T lymphocytes downregulate expression of the transcription factor KLF2. KLF2 expression remains low as these cells differentiate to Cytotoxic T lymphocytes (CTL) but may be re-expressed depending on the local environmental signals. We used retroviral transduction to enforce KLF2 expression in CTL to determine the impact of it re-expression on the CTL genetic program. T lymphocytes with a transgenic T cell receptor (P14 LCMV) isolated from murine spleens were activated with gp33-41 peptide for 2 days and transduced with empty vector (evGFP) or GFP-KLF2. After differentiation to CTL in culture with Interleukin-2 for 2 further days, cells positive for GFP were isolated by Fluorescence Activated Cell Sorting and the RNA extracted for microarray analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Gavin Preston

PROVIDER: E-GEOD-26568 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Impact of KLF2 expression on T cell genetic program

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Expression data from P14 TCR cytotoxic T cells overexpressing HDAC7 phosphorylation deficient mutant

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Transcriptional profiling by array of Klf2 wild-type and Klf2-Null mESCs cultured under 2i

Project description:The self-renewing pluripotent state was first captured in mouse embryonic stem cells (mESCs) over two decades ago. The standard condition requires the presence of serum and LIF, which provide growth promoting signals for cell expansion. However, there are pro-differentiation signals which destabilize the undifferentiated state of mESCs. The dual inhibition (2i) of the pro-differentiation Mek/Erk and Gsk3/Tcf3 pathways in mESCs is sufficient to establish an enhanced pluripotent “ground state” which bears features resembling the pre-implantation mouse epiblast. Gsk3 inhibition alleviates the repression of Esrrb, a transcription factor that can substitute for Nanog function in mESCs. The molecular mechanism that is mediated by Mek inhibition is however not clear. In this study, we investigate the pathway through which Mek inhibition operates to maintain ground state pluripotency. We have found that in mESCs, Kruppel-like factor 2 (Klf2) is a protein target of the Mek/Erk pathway; and that Klf2 protein is phosphorylated by Erk2 and subsequently degraded through the proteosome. It is therefore by Mek-inhibition through PD0325901 or 2i that enables the stabilization and accumulation of Klf2 to sustain ground state pluripotency. Importantly, we found that Klf2-null mESCs, while viable under LIF/Serum conditions, cannot be maintained and eventually gradually die within a few passages. Our result thus demonstrates that Klf2 is an essential factor of ground state pluripotency. Collectively, our study defines the Mek/Klf2 axis that cooperates with the Gsk3/Esrrb pathway in mediating ground state pluripotency.

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