T-cell receptor signal strength and epigenetic control of Bim predict memory CD8+T-cell fate

Most effector CD8+T cells die, while some persist and become either “effector” (TEM) or “central” (TCM) memory T cells. Paradoxically, effector CD8+T cells with greater memory potential have higher levels of the pro-apoptotic molecule Bim. Here, we report, using a novel Bim-mCherry knock-in mouse, that cells with high levels of Bim preferentially develop into TCMcells. Bim levels remained stable and were regulated by DNA methylation at the Bim promoter. Notably, high levels of Bcl-2 were required for Bimhicells to survive. Using Nur77-GFP mice as an indicator of TCR signal strength, Nur77 levels correlated with Bim expression and Nur77hicells also selectively developed into TCMcells. Altogether, these data show that Bim levels and TCR signal strength are predictive of TEM- vs. TCM-cell fate. Further, given the many other biologic functions of Bim, these mice will have broad utility beyond CD8+T-cell fate.