Abstract: Methods and compositions are provided for inhibiting the responsiveness of CD4+ T cells that have been sensitized to antigen, i.e. CD4+ memory, or effector T cells. It is shown herein that such effector T cells will fail to proliferate in response to antigen when inhibited by two compounds, which act on two distinct signaling pathways, the mTOR pathway and the MAPK (MEK) pathway. A synergistic combination of inhibitors is required to achieve effector T cell inactivation because a single inhibitor can provide for inactivation of naïve CD4+ T cells, but will not by itself inactivate the sensitized effector T cells.