mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation
What this study shows
By deleting Tsc2, Rheb or Rictor in T cells, this work split the CD8 response between the two mTOR complexes. Tsc2 loss left mTORC1 constitutively active: the cells were strongly glycolytic (high ECAR, high Slc2a1 and Pfk1, low spare respiratory capacity), made more IFN-gamma, TNF and granzyme B, cleared EL4 thymoma and slowed B16-OVA growth, but stayed terminally differentiated and were about two-fold fewer than wild type at day 30, with no memory. Rheb loss removed mTORC1 activity with mTORC2 intact: those cells failed as effectors but kept memory-like features and were about two-fold more numerous at day 30, yet did not respond to rechallenge, which the authors trace to metabolic defects. Rapamycin from day 5 (100 ug/kg daily) rescued survival of Tsc2-deficient cells, raised CD127 and Eomesodermin, lowered KLRG1 and T-bet and restored a recall response. Losing mTORC2 by Rictor deletion left effector function intact but increased memory cells that still responded 133 days after infection, and the Tsc2/Rictor double knockout showed that the hyperactive effector phenotype needs mTORC2. Boundary: mouse genetics with TCR-transgenic transfers and transplantable tumours; the comparison rests on genetic extremes (no TSC2, no Rheb, no Rictor) rather than graded physiological signalling, and nothing here is measured in people.
At a glance
| Evidence type | A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Mice with T-cell-specific deletion of Tsc2, Rheb or Rictor (and Tsc2/Rictor double knockout), OT-I adoptive transfer, vaccinia-OVA and Listeria-OVA infection, EL4 and B16-OVA tumour models, rapamycin (100 ug/kg/day) and 2-deoxyglucose in vivo, Seahorse metabolic profiling); the code names the system studied -- animal work can be rigorous and still not be human data. |
| Study type | 4 - Animal Study |
| Model system | Mice with T-cell-specific deletion of Tsc2, Rheb or Rictor (and Tsc2/Rictor double knockout), OT-I adoptive transfer, vaccinia-OVA and Listeria-OVA infection, EL4 and B16-OVA tumour models, rapamycin (100 ug/kg/day) and 2-deoxyglucose in vivo, Seahorse metabolic profiling |
| Journal | Journal of Clinical Investigation |
| Year | 2015 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1172/JCI77746 · PMID 25893604 · Free full text (PMC4463194) |
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | T-cell-specific deletion of Tsc2, Rheb or Rictor; Tsc2/Rictor double deletion; rapamycin 100 ug/kg/day; 2-deoxyglucose 500 mg/kg/day |
| Target | mTORC1 and mTORC2 activity in CD8 T cells and the effector versus memory decision |
| Model | Mouse |
| Effect | Constitutive mTORC1 drives glycolytic effectors that cannot become memory; loss of mTORC1 blocks effector differentiation; loss of mTORC2 increases functional memory |
In the Atlas
Related topics
Links in the pathway map
- Supports Rictor required-for mTORC2
- Supports TSC1/TSC2 inhibits mTORC1
More studies on this topic
- The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2 (2011)
- The role of mTORC2/RICTOR in immune cells and inflammatory diseases. (2026)
- PTEN regulates microtubule polymerization via mTORC2, but not mTORC1, in peripheral sensory neurons (2026)
- The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C (2008)
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