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Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner

Lianjun Zhang1, Benjamin O Tschumi1, Isabel C Lopez-Mejia2

  • 1Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.

Cell Reports
|January 26, 2016
PubMed

Insights

Mammalian target of rapamycin complex 2 (mTORC2) regulates CD8 T cell differentiation. Its deficiency enhances memory formation and recall responses, offering potential immunotherapy targets.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • CD8 T cell activation upon infection leads to short-lived effector cells (SLECs) and memory precursor cells (MPECs).
  • The signaling pathways governing this differentiation are not fully understood.
  • Mammalian target of rapamycin complex 2 (mTORC2) is a key signaling complex.

Purpose of the Study:

  • To investigate the role of Rictor, a core component of mTORC2, in CD8 T cell differentiation.
  • To elucidate the molecular mechanisms by which mTORC2 influences T cell fate.

Main Methods:

  • Utilized Rictor knockout (KO) models.
  • Analyzed CD8 T cell differentiation, effector functions, and memory formation.
  • Assessed gene expression (Eomes, Tcf-1, T-bet), mitochondrial respiration, fatty acid oxidation, and Foxo1 activity.

Main Results:

  • Rictor deficiency promoted memory precursor cell (MPEC) commitment over short-lived effector cell (SLEC) differentiation.
  • mTORC2-deficient CD8 T cells showed enhanced IL-2 secretion, potent recall responses, and improved effector functions.
  • Key findings included Eomes/Tcf-1 upregulation, T-bet repression, enhanced mitochondrial function, and Foxo1 nuclear stabilization.

Conclusions:

  • mTORC2 is a critical regulator of CD8 T cell differentiation, favoring effector cell fate.
  • Rictor deficiency enhances memory formation and recall responses through Foxo1-mediated transcriptional and metabolic reprogramming.
  • mTORC2 inhibition represents a potential therapeutic strategy for enhancing T cell-based immunotherapies.
Keywords:
CD8 T cellFoxo1RictorinfectionmTORC2

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