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

Abstract

Most effector CD8⁺ T cells die, while some persist and become either "effector" (T_EM) or "central" (T_CM) 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 T_CM cells. Bim levels remained stable and were regulated by DNA methylation at the Bim promoter. Notably, high levels of Bcl-2 were required for Bim^hi cells to survive. Using Nur77-GFP mice as an indicator of TCR signal strength, Nur77 levels correlated with Bim expression and Nur77^hi cells also selectively developed into T_CM cells. Altogether, these data show that Bim levels and TCR signal strength are predictive of T_EM- vs. T_CM-cell fate. Further, given the many other biologic functions of Bim, these mice will have broad utility beyond CD8⁺ T-cell fate.