Impaired Mitochondrial Oxidative Phosphorylation Limits The Self-renewal Of T-cells Exposed To Persistent Antigen.
Vardhana SA, Hwee MA, Berisa M, Wells DK, Yost KE, King B, Smith M, Herrer PS, Chang HY, Satpathy AT, van den Brink MRM, Cross JR, Thompson CB.
Nat Immunol. 2020 Jul 13. doi: 10.1038/s41590-020-0725-2. PMID: 32661364
The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion.
Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.