TOX transcriptionally and epigenetically programs CD8 T cell exhaustion.

Khan O , Giles JR , McDonald S , Manne S , Ngiow SF , Patel KP , Werner MT , Huang AC , Alexander KA , Wu JE , Attanasio J , Yan P , George SM , Bengsch B , Staupe RP , Donahue G , Xu W , Amaravadi RK , Xu X , Karakousis GC , Mitchell TC , Schuchter LM ,
Giornale di psichiatria e di neuropatologia
Exhausted CD8 T cells (T) in chronic infections and cancer have limited effector function, high inhibitory receptor co-expression and extensive transcriptional changes compared to effector (T) or memory (T) CD8 T cells. T are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T are a distinct immune subset, with a unique chromatin landscape compared to T and T. However, the mechanisms governing the transcriptional and epigenetic development of T remain unknown. Here, we identify the HMG-box transcription factor TOX as a central regulator of T. TOX is largely dispensable for T and T formation, but is critical for exhaustion and without TOX T do not form. TOX is induced by calcineurin and NFAT2 and operates in a feed-forward loop to become calcineurin independent and sustained in T. Thus, robust TOX expression results in commitment to T by translating persistent stimulation into a distinct T transcriptional and epigenetic developmental program.

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