![]() ![]() ![]() TOX was expressed at low levels early after Listeria infection but declined to baseline levels (by day 5 after infection) and remained low in memory T cells ( Fig. To assess TOX expression during CD8 T cell differentiation in acute infection and tumorigenesis, congenically marked naive TCR TAG cells were transferred into (i) wild-type C57BL/6 (B6) mice immunized with LmTAG, or (ii) tamoxifen-inducible liver cancer mice (AST×Cre-ER T2 AST denotes albumin-floxStop-SV40 large T antigen) treated with tamoxifen ( Fig. Although TOX is required during thymic development of CD4 + T lineage cells, natural killer and innate lymphoid cells 10– 12, and in regulating CD8 T cell-mediated autoimmunity 13, its role in tumour-induced T cell dysfunction is unknown. TOX is a nuclear DNA-binding factor and a member of the high-motility group box superfamily that is thought to bind DNA in a sequence-independent but structure-dependent manner 9. We analysed our RNA sequencing (RNA-seq) data 5 and found that the gene encoding the nuclear factor TOX was highly expressed in dysfunctional TCR TAG cells, but low in functional naive, effector and memory TCR TAG cells ( Fig. However, many of these transcription factors are also crucial for the development of normal effector and memory T cells 8 thus, we set out to identify transcription factors that were specifically expressed in dysfunctional TCR TAG cells. Numerous transcription factors were dysregulated in dysfunctional TCR TAG cells (such as NFAT, TCF-1, LEF1, IRF4 and BLIMP1) compared with functional effector or memory TCR TAG cells generated during acute infection with Listeria (using a recombinant Listeria monocytogenes strain that expressed TAG epitope I ( LmTAG)) 5. 1a), we recently showed that CD8 + T cells expressing a restricted T cell receptor (TCR) specific for TAG (hereafter referred to as TCR TAG cells) differentiate to an epigenetically encoded dysfunctional state, exhibiting hallmarks of TST cell dysfunction including the expression of inhibitory receptors and loss of effector cytokines 3, 5. Using an inducible model of autochthonous liver cancer in which SV40 large T antigen (TAG) is the oncogenic driver and tumour-specific antigen 7 ( Fig. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. Despite their normal, ‘non-exhausted’ immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states 1– 6.
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