Uncovering the mechanisms involved in CD8 T-cell dysfunction mediated by tryptophan catabolism using CRISPR knockout screening

Indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO) are enzymes responsible for catalyzing tryptophan into kynurenine. Their expression contributes to tumor immune evasion by preventing antitumor T-lymphocyte responses. However, the mechanisms leading to T-cell dysfunction mediated by tryptophan catabolism remain under debate. Our work aimed to elucidate these mechanisms using genome-wide CRISPR/Cas9 screening. Most screening target genes were related to mitochondrial function, leading us to investigate the impact of tryptophan deprivation on T cell metabolism. We observed that CD8 T cells, when activated under tryptophan deprivation, fail to shift their metabolism towards glycolysis and instead rely on oxidative phosphorylation for energy production. Since the activation-induced metabolic reprogramming is essential to promote T cell proliferation, our results provide a mechanistic rationale to explain T cell proliferation arrest mediated by tryptophan deprivation.