Activated T cells degrade extracellular proteins to enhance effector functions

Area of Science:

• Immunology
• Cell Biology
• Metabolism

Background:

• Extracellular proteins are abundant amino acid sources in body fluids.
• The role of extracellular protein breakdown in T cell immunity is unclear.

Purpose of the Study:

• To investigate how extracellular protein catabolism impacts T cell activation and immunity.
• To elucidate the role of TFE3 in regulating this pathway.

Main Methods:

• Studied T cell activation in vitro and in vivo.
• Utilized genetic ablation of Tfe3.
• Analyzed lysosomal gene expression, mTORC1 signaling, and T cell function.
• Examined tumor-infiltrating T cells from lung cancer patients of different ages.

Main Results:

• Activated T cells use endocytosed extracellular proteins as an amino acid source, sustaining mTORC1 activity and cytokine production.
• Tfe3 deficiency impairs extracellular protein catabolism, reduces mTORC1 signaling, and compromises T cell anti-viral and anti-tumor responses.
• Tumor-infiltrating T cells in older lung cancer patients show reduced lysosomal function and cytokine secretion, which can be restored by Vismodegib.

Conclusions:

• Lysosome-mediated extracellular protein catabolism is a key metabolic pathway supporting T cell immunity.
• The TFE3-protein-mTORC1 axis is vital for effective T cell responses and has clinical implications in aging and cancer.