Localization of a TORC1-eIF4F translation complex during CD8 + T cell activation drives divergent cell fate

Activated CD8 T lymphocytes differentiate into heterogeneous subsets. Using super-resolution imaging, we found that prior to the first division, dynein-dependent vesicular transport polarized active TORC1 toward the microtubule-organizing center (MTOC) at the proximal pole. This active TORC1 was phy...

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Bibliographic Details
Published inMolecular cell Vol. 82; no. 13; pp. 2401 - 2414.e9
Main Authors Liedmann, Swantje, Liu, Xueyan, Guy, Clifford S, Crawford, Jeremy Chase, Rodriguez, Diego A, Kuzuoğlu-Öztürk, Duygu, Guo, Ao, Verbist, Katherine C, Temirov, Jamshid, Chen, Mark J, Ruggero, Davide, Zhang, Hui, Thomas, Paul G, Green, Douglas R
Format Journal Article
LanguageEnglish
Published United States 07.07.2022
Subjects
CD8-Positive T-Lymphocytes
Cell Differentiation
Eukaryotic Initiation Factor-4F
Lymphocyte Activation
Mechanistic Target of Rapamycin Complex 1 - genetics
STORM
asymmetric cell division
scRNA-seq
c-Myc
STED
cell fate
translation
polarization
CD8(+) T cells
eIF4A
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Summary:Activated CD8 T lymphocytes differentiate into heterogeneous subsets. Using super-resolution imaging, we found that prior to the first division, dynein-dependent vesicular transport polarized active TORC1 toward the microtubule-organizing center (MTOC) at the proximal pole. This active TORC1 was physically associated with active eIF4F, required for the translation of c-myc mRNA. As a consequence, c-myc-translating polysomes polarized toward the cellular pole proximal to the immune synapse, resulting in localized c-myc translation. Upon division, the TORC1-eIF4A complex preferentially sorted to the proximal daughter cell, facilitating asymmetric c-Myc synthesis. Transient disruption of eIF4A activity at first division skewed long-term cell fate trajectories to memory-like function. Using a genetic barcoding approach, we found that first-division sister cells often displayed differences in transcriptional profiles that largely correlated with c-Myc and TORC1 target genes. Our findings provide mechanistic insights as to how distinct T cell fate trajectories can be established during the first division.
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Lead Contact
S.L. conceived the project, designed, and performed most experiments, interpreted results, and co-wrote the manuscript. X.L. and H.Z. analyzed STORM data. C.S.G. performed STORM imaging and expansion microscopy. J.C.C. and P.G.T. contributed to the design of the scRNAseq experiments, analyzed data, interpreted results, and co-wrote the manuscript. D.A.R. performed co-immunoprecipitation experiments. D.K.O. and D.R. contributed to the design of ribosome fractionation experiments, performed experiments, and interpreted results. A.G. performed imaging and CUT&RUN experiments. M.C. analyzed CUT&RUN data. K.C.V. performed in vivo experiments, J.T. performed STED imaging. D.R.G. conceived the project, supervised experimental designs, interpreted results, and co-wrote the manuscript.
Author contributions
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2022.04.016