2. Academic Validation
  3. Localization of a TORC1-eIF4F translation complex during CD8+ T cell activation drives divergent cell fate

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

  • Mol Cell. 2022 Jul 7;82(13):2401-2414.e9. doi: 10.1016/j.molcel.2022.04.016.
Swantje Liedmann 1,  Xueyan Liu 2,  Clifford S Guy 3,  Jeremy Chase Crawford 3,  Diego A Rodriguez 3,  Duygu Kuzuoğlu-Öztürk 4,  Ao Guo 3,  Katherine C Verbist 3,  Jamshid Temirov 5,  Mark J Chen 3,  Davide Ruggero 6,  Hui Zhang 7,  Paul G Thomas 3,  Douglas R Green 8
Affiliations

Affiliations

  • 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: swantje.liedmann@stjude.org.
  • 2 Department of Mathematics, University of New Orleans, New Orleans, LA 70148, USA.
  • 3 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4 Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 5 Department of Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 6 Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 7 Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 8 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.
PMID: 35597236 DOI: 10.1016/j.molcel.2022.04.016
Abstract

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.

Keywords

CD8(+) T cells; STED; STORM; asymmetric cell division; c-Myc; cell fate; eIF4A; polarization; scRNA-seq; translation.

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