mTORC1 and mTORC2 selectively regulate CD8⁺ T cell differentiation.

Area of Science:

• Immunology
• Cell Biology
• Metabolism

Background:

• Mammalian target of rapamycin (mTOR) signaling is crucial for T cell differentiation.
• mTOR exists in two complexes, mTORC1 and mTORC2, with distinct functions.
• Understanding the specific roles of mTORC1 and mTORC2 in CD8+ T cell subsets is essential for immune response modulation.

Purpose of the Study:

• To elucidate the distinct roles of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) in CD8+ T cell effector and memory generation.
• To investigate the impact of mTOR pathway dysregulation on T cell metabolism and function.
• To explore the potential of targeting mTOR pathways for enhancing vaccine efficacy and antitumor immunity.

Main Methods:

• Utilized genetically modified mice with T cell-specific deletions of key regulators of mTORC1, such as tuberous sclerosis complex 2 (TSC2) and RAS homolog enriched in brain (RHEB).
• Assessed CD8+ T cell differentiation, metabolic profiles (glycolysis, metabolic rate), and memory cell generation.
• Investigated the effects of mTORC2 inhibition on CD8+ T cell memory development and function.

Main Results:

• Constitutive mTORC1 activation (TSC2 deletion) promoted potent effector CD8+ T cells but impaired memory formation due to terminal differentiation.
• Loss of mTORC1 activity (RHEB deletion) resulted in memory-like CD8+ T cells with impaired recall responses due to metabolic defects.
• mTORC2 activity was found to regulate CD8+ T cell memory, and its inhibition enhanced memory cell generation through metabolic reprogramming.

Conclusions:

• mTORC1 and mTORC2 play distinct and critical roles in governing CD8+ T cell effector versus memory cell fate.
• The interplay between mTOR signaling, cellular metabolism, and T cell differentiation is key to generating effective adaptive immune responses.
• Targeting specific mTOR complexes offers a promising strategy for optimizing T cell-based immunotherapies and vaccines.