Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection

Abstract

Progenitor-like CD8 + T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including TCF1, but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing single-cell transcriptomes and epigenetic profiles of CD8 + T cells responding to acute and chronic viral infections, we found that progenitor-like CD8 + T cells became distinct from memory precursors before the peak of the T-cell response. We discovered a co-expression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursors. Moreover, TOX promoted persistence of antiviral CD8 + T cells and was required for the programming of progenitor-like CD8 + T cells. Thus, long-term CD8 + T-cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.

Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells

“…One explanation for the limited efficacy of PD-1/PD-L1 blockade relates to its inability to reverse the exhaustion-associated epigenetic imprint (Pauken et al, 2016). Recent studies have identified TOX, TOX2, and AP-1 family members as central regulators of human T cell exhaustion that promote widespread transcriptional and epigenetic dysregulation (Alfei et al, 2019;Khan et al, 2019;Scott et al, 2019;Seo et al, 2019;Wang et al, 2019;Yao et al, 2019). These findings have enabled new approaches to mitigate exhaustion, including enforced expression of c-Jun or CRISPR-mediated deletion of TOX, TOX2, or NR4A family TFs (Chen et al, 2019a;Seo et al, 2019).…”

Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

“…A likely explanation is that the EM-like compartment is enriched in non tumor-specific cells, as multiple studies have shown the presence of large numbers of "bystander" T cells in human tumors (Simoni et al, 2018;Scheper et al, 2019) Figure 6 D), which is essential to establish and maintain the epigenetic T cell exhaustion program enabling T cells to persist in the context of chronic antigenic stimulation (Alfei et al, 2019;Khan et al, 2019;Scott et al, 2019;Yao et al, 2019).…”

“…Unsupervised clustering on the high-dimensional space revealed the presence of four robust CD8 TIL clusters with distinct transcriptomic profiles. Cluster 1 (C1) was defined by high expression of inhibitory receptors Pdcd1, Havcr2, Ctla4, Tigit and Lag3, exhaustion-related transcription factors such as Batf and Tox (Alfei et al, 2019;Khan et al, 2019;Scott et al, 2019;Yao et al, 2019) and high expression of cytotoxic molecules (e.g. Gzmb,Prf1,Fasl), compatible with an exhausted state (Figure 1 B,C).…”

Dissecting the human immune system with single cell RNA sequencing technology

“…Recently, TOX protein was found to regulate the expression of multiple inhibitory molecules including PD-1, Lag-3, and Tim-3, and determine the survival of dysfunctional/exhausted T cells using scRNA-seq. 74 Three other groups also independently confirmed the findings. [75][76][77] As for cancer, metallothionein 1 (MT1) was identified as the topranking gene in dysfunctional CD8 + T cells using SMART2-seq.…”

“…Identifying core transcriptional signatures of dysfunctional T cells may help developing therapies against chronic infection and cancer. Recently, TOX protein was found to regulate the expression of multiple inhibitory molecules including PD‐1, Lag‐3, and Tim‐3, and determine the survival of dysfunctional/exhausted T cells using scRNA‐seq . Three other groups also independently confirmed the findings …”