Research ArticleT CELLS

TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells

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Science Immunology  03 Jul 2020:
Vol. 5, Issue 49, eaba7918
DOI: 10.1126/sciimmunol.aba7918

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The TOX profiles of T cells

Transcription factors TOX and TCF-1 have emerged as key drivers of exhaustion and stemness programs in CD8+ T cells. Using bulk and single-cell transcriptome analyses and flow cytometric analyses, Sekine et al. have generated a detailed map of TOX and TCF-1 expression in human CD8+ T cells. TOX is generally expressed by effector memory CD8+ T cells and is not restricted to exhausted T cells, whereas TCF-1 demarcates early-differentiated, memory CD8+ T cells. Using tetramers to examine the specificity of antigen-specific CD8+ T cells, they found that cytotoxic memory CD8+ T cells targeting both pathogenic and well-controlled chronic infections are more likely to express TOX. Their results propose that TOX-dependent transcriptional wiring is not restricted to exhausted CD8+ T cells.


CD8+ T cell exhaustion is a hallmark of many cancers and chronic infections. In mice, T cell factor 1 (TCF-1) maintains exhausted CD8+ T cell responses, whereas thymocyte selection-associated HMG box (TOX) is required for the epigenetic remodeling and survival of exhausted CD8+ T cells. However, it has remained unclear to what extent these transcription factors play analogous roles in humans. In this study, we mapped the expression of TOX and TCF-1 as a function of differentiation and specificity in the human CD8+ T cell landscape. Here, we demonstrate that circulating TOX+ CD8+ T cells exist in most humans, but that TOX is not exclusively associated with exhaustion. Effector memory CD8+ T cells generally expressed TOX, whereas naive and early-differentiated memory CD8+ T cells generally expressed TCF-1. Cytolytic gene and protein expression signatures were also defined by the expression of TOX. In the context of a relentless immune challenge, exhausted HIV-specific CD8+ T cells commonly expressed TOX, often in clusters with various activation markers and inhibitory receptors, and expressed less TCF-1. However, polyfunctional memory CD8+ T cells specific for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) also expressed TOX, either with or without TCF-1. A similar phenotype was observed among HIV-specific CD8+ T cells from individuals who maintained exceptional immune control of viral replication. Collectively, these data demonstrate that TOX is expressed by most circulating effector memory CD8+ T cell subsets and not exclusively linked to exhaustion.

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