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Metabolic and epigenetic regulation of T-cell exhaustion.
Nature Metabolism  (IF13.511),  Pub Date : 2020-09-21, DOI: 10.1038/s42255-020-00280-9
Fabien Franco,Alison Jaccard,Pedro Romero,Yi-Ru Yu,Ping-Chih Ho

Current immunotherapies yield remarkable clinical outcomes by boosting the power of host immunity in cancer cell elimination and viral clearance. However, after prolonged antigen exposure, CD8+ T cells differentiate into a special differentiation state known as T-cell exhaustion, which poses one of the major hurdles to antiviral and antitumor immunity during chronic viral infection and tumour development. Growing evidence indicates that exhausted T cells undergo metabolic insufficiency with altered signalling cascades and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to immune-checkpoint-blockade therapies. How metabolic stress affects T-cell exhaustion remains unclear; therefore, in this Review, we summarize current knowledge of how T-cell exhaustion occurs, and discuss how metabolic insufficiency and prolonged stress responses may affect signalling cascades and epigenetic reprogramming, thus locking T cells into an exhausted state via specialized differentiation programming.