Programmed death-1 controls T cell survival by regulating oxidative metabolism

Area of Science:

• Immunology
• Cellular Metabolism
• Cancer Immunotherapy

Background:

• Programmed death-1 (PD-1) is a coinhibitory receptor crucial for immune homeostasis, regulating T cell function and survival.
• PD-1 blockade exacerbates graft-versus-host disease (GVHD), but its impact on T cell metabolism remains unclear.

Purpose of the Study:

• To investigate the relationship between PD-1 signaling and T cell metabolism, specifically reactive oxygen species (ROS) production.
• To elucidate the mechanisms by which PD-1 influences T cell survival and metabolic susceptibility.

Main Methods:

• Analysis of PD-1 expression and ROS levels in murine and human alloreactive T cells post-allogeneic bone marrow transplantation.
• Assessment of ROS levels following PD-1 blockade, with and without etomoxir (fatty acid oxidation inhibitor).
• Evaluation of T cell survival in response to antioxidants and the impact of PD-1 blockade on metabolic inhibition efficacy.

Main Results:

• Alloreactive T cells upregulated both PD-1 and ROS after transplantation, a phenotype specific to alloreactive cells.
• PD-1 blockade reduced mitochondrial and total cellular ROS, dependent on fatty acid oxidation.
• Elevated ROS downstream of PD-1 impaired T cell survival and reduced susceptibility to subsequent metabolic inhibition.

Conclusions:

• PD-1 signaling promotes apoptosis in alloreactive T cells by increasing ROS through fatty acid oxidation.
• PD-1 blockade diminishes the potential for subsequent metabolic inhibition, a critical factor for anti-PD-1 therapies.