TOX transcriptionally and epigenetically programs CD8.sup.+ T cell exhaustion

Exhausted CD8.sup.+ T (T.sub.ex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T.sub.eff) or memory (T.sub.mem) CD8.sup.+ T cells. T.sub.ex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T.sub.ex cells are a distinct immune subset, with a unique chromatin landscape compared with T.sub.eff and T.sub.mem cells. However, the mechanisms that govern the transcriptional and epigenetic development of T.sub.ex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T.sub.ex cells in mice. TOX is largely dispensable for the formation of T.sub.eff and T.sub.mem cells, but it is critical for exhaustion: in the absence of TOX, T.sub.ex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in T.sub.ex cells. Robust expression of TOX therefore results in commitment to T.sub.ex cells by translating persistent stimulation into a distinct T.sub.ex cell transcriptional and epigenetic developmental program. The transcription factor TOX is a central regulator of the transcriptional and epigenetic development of exhausted T cells.
Author(s): Omar Khan [sup.1] [sup.2] [sup.3] [sup.14] , Josephine R. Giles [sup.1] [sup.2] [sup.3] , Sierra McDonald [sup.4] [sup.5] [sup.6] , Sasikanth Manne [sup.1] [sup.2] , Shin Foong Ngiow [sup.1] [...]