T-Cells Null for the MED23 Subunit of Mediator Express Decreased Levels of KLF2 and Inefficiently Populate the Peripheral Lymphoid Organs

<div><p>MED23, a subunit of the Mediator coactivator complex, is important for the expression of a subset of MAPK/ERK pathway-responsive genes, the constituents of which vary between cell types for reasons that are not completely clear. MAPK/ERK pathway-dependent processes are essential for T-cell development and function, but whether MED23 has a role in this context is unknown. We generated <i>Med23</i> conditional knockout mice and induced <i>Med23</i> deletion in early T-cell development using the lineage specific <i>Lck-Cre</i> transgene. While the total cell number and distribution of cell populations in the thymuses of <i>Med23^flox/flox;Lck-Cre</i> mice were essentially normal, MED23 null T-cells failed to efficiently populate the peripheral lymphoid organs. MED23 null thymocytes displayed decreased expression of the MAPK/ERK-responsive genes <i>Egr1</i>, <i>Egr2</i>, as well as of the membrane glycoprotein <i>Cd52</i> (CAMPATH-1). MED23 null CD4 single-positive thymocytes also showed decreased expression of KLF2 (LKLF), a T-cell master regulatory transcription factor. Indeed, similarities between the phenotypes of mice lacking MED23 or KLF2 in T-cells suggest that KLF2 deficiency in MED23 null T-cells is one of their key defects. Mechanistic experiments using MED23 null MEFs further suggest that MED23 is required for full activity of the MAPK-responsive transcription factor MEF2, which has previously been shown to mediate <i>Klf2</i> expression. In summary, our data indicate that MED23 has critical roles in enabling T-cells to populate the peripheral lymphoid organs, possibly by potentiating MEF2-dependent expression of the T-cell transcription factor KLF2.</p>