Work

Activated T cells degrade extracellular proteins to enhance effector functions

Year: 2025

Type: article

Abstract: Proteins are the most abundant source of amino acids in body fluids. However, the potential contribution of extracellular protein catabolism to the regulation of T cell immunity remains poorly understood. In this study, we show that endocytosed extracellular proteins function as an amino acid source in activated T cells, maintaining mTORC1 activity and sustaining cytokine production following T cell activation. Genetic ablation of Tfe3 impairs the activation-induced upregulation of lysosomal genes and disrupts extracellular protein catabolism, resulting in attenuated mTORC1 signaling and compromised anti-viral and anti-tumor T cell responses. The TFE3-protein-mTORC1 signaling axis demonstrates clinical relevance. CD8 + PD-1 + tumor-infiltrating T cells from older patients with lung cancer display reduced lysosomal degradation capacity and impaired cytokine secretion compared to their middle-aged counterparts. This functional defect is rescued by treatment with Vismodegib, a TFE3-inducing drug. Our findings reveal lysosome-mediated extracellular protein catabolism as an important metabolic pathway supporting T cell immunity. • Activated T cells constitutively internalize albumin in both humans and mice • Lysosomal degradation of extracellular proteins potentiates T cell responses • TFE3 orchestrates lysosomal biogenesis and extracellular protein catabolism • Aged TILs exhibit impaired lysosomal proteolysis and cytokine production Yin et al. demonstrate that extracellular proteins internalized via macropinocytosis serve as an amino acid reservoir in activated T cells, supporting mTORC1 activity and sustaining cytokine production after T cell activation. Notably, this metabolic pathway is impaired in tumor-infiltrating T cells from older patients with lung cancer.

Source: Cell Reports

DOI: 10.1016/j.celrep.2025.116797