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 towards 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. Overall design: CTV-labeled GFP-c-Myc OT-I CD8+ T cells were activated on peptide-pulsed APCs for 36 h. First-division GFP-c-Mychigh and GFP-c-Myclow cell populations (CD8+, CTV 2nd peak, highest and lowest 20% GFP-c-Myc) were sorted into medium with or without 200 nM Silvestrol and cultured for additional 2 h.