FoxP3 Mediated Induction of Pim 2 Allows T Regulatory Cells to Preferentially Expand in Rapamycin

Abstract

Addition of rapamycin to cultures of expanding T regulatory cells helps maintain their suppressive activity, but the mechanism behind this observation is unclear. Human pim 2, similar to murine pim 2, is a serine/threonine kinase that can confer rapamycin resistance. Unexpectedly, pim 2 was found to be constitutively expressed in freshly isolated, resting T regulatory cells but not in CD4 T effector cells, explaining why addition of rapamycin prior to T cell activation favors T regulatory cell expansion. Introduction of FoxP3, but not FoxP3Ä2, into effector CD4 T cells induced pim 2 expression and conferred preferential expansion in the presence of rapamycin, indicating that FoxP3 can regulate pim 2 expression and that functional differences do exist between the two prominent FoxP3 isoforms. Finally, we correlated the ability of natural T regulatory cells to expand with FoxP3 expression and observed positive correlation in the presence of rapamycin and a negative correlation in the absence of rapamycin. Together, these results indicate that T regulatory cells, because of their constitutive expression of FoxP3, are programmed to be resistant to rapamycin and this provides further rationale why this immunosuppressant drug should be used to augment T regulatory activity.