TY - JOUR
T1 - T-cell receptor signal strength and epigenetic control of Bim predict memory CD8+ T-cell fate
AU - Li, Kun Po
AU - Ladle, Brian H.
AU - Kurtulus, Sema
AU - Sholl, Allyson
AU - Shanmuganad, Sharmila
AU - Hildeman, David A.
N1 - Funding Information:
Acknowledgements Grant support was provided by NIH RO1 AI057753, NIH RO1 AI109810, NIH RO1 AG03357, and NIH RO1 DK081175 (DAH).
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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 TCM cells. Bim levels remained stable and were regulated by DNA methylation at the Bim promoter. Notably, high levels of Bcl-2 were required for Bimhi cells to survive. Using Nur77-GFP mice as an indicator of TCR signal strength, Nur77 levels correlated with Bim expression and Nur77hi cells also selectively developed into TCM cells. 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.
AB - 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 TCM cells. Bim levels remained stable and were regulated by DNA methylation at the Bim promoter. Notably, high levels of Bcl-2 were required for Bimhi cells to survive. Using Nur77-GFP mice as an indicator of TCR signal strength, Nur77 levels correlated with Bim expression and Nur77hi cells also selectively developed into TCM cells. 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.
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U2 - 10.1038/s41418-019-0410-x
DO - 10.1038/s41418-019-0410-x
M3 - Article
C2 - 31558776
AN - SCOPUS:85073973353
VL - 27
SP - 1214
EP - 1224
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 4
ER -