Take my breath away—mitochondrial dysfunction drives CD8+ T cell exhaustion
Felix Clemens Richter, Mariia Saliutina, Ahmed N. Hegazy, Andreas Bergthaler
Abstract
CD8 + T cell exhaustion is a phenomenon often observed in individuals battling chronic diseases like cancer and chronic viral infections. Prolonged exposure to antigens desensitizes CD8 + T cells, leading to a diminished capacity to mount effector responses. This state of exhaustion is characterized by decreased expression and secretion of cytolytic proteins and cytokines, coupled with upregulation of inhibitory receptors (e.g., PD-1, TIM-3, LAG-3) [ 1 ]. T cell exhaustion unfolds along a trajectory where progenitor exhausted CD8 + T cells (T PEX ) give rise to a larger number of terminally exhausted CD8 + T cells (T EX ) [ 2 ]. Modern cancer therapy aims to re-invigorate pre-existing exhausted T cells by blocking its inhibitory receptors, which is known as immune checkpoint inhibition (ICI) therapy. T PEX are most amendable to ICI therapy, which then give rise to a substantial burst of functional CD8 + T cells and thus driving anti-tumor responses [ 3 ]. However, not all patients respond to ICI therapy and thus creating a further need to identify crucial factors that drive CD8 + T cell exhaustion to enhance the efficacy ICI therapy.