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

• Published in: Molecular cell 2022-07, Vol.82 (13), p.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: Article
• Language: English
• Subjects: CD8-Positive T-Lymphocytes; Cell Differentiation; Eukaryotic Initiation Factor-4F; Lymphocyte Activation; Mechanistic Target of Rapamycin Complex 1 - genetics
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2022.04.016

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.