Sekine, Perez-Potti, and Nguyen et al. investigated the expression of transcription factors TOX and TCF-1 in CD8+ T cells from virus-infected humans. Unlike the strong association of TOX with exhaustion in mice, in humans TOX was a marker of chronic memory and not restricted to exhausted CD8+ T cells. TOX was widely expressed in circulating Tem and Temra CD8+ T cells rich in cytolytic genes, as well as in polyfunctional memory CD8+ T cells from chronic virally infected (EBV, CMV, or HIV) donors with effective immune control. TCF-1 was mostly expressed in naive and early-differentiated memory CD8+ T cells and helped define TOX+ sub-populations.
Contributed by Katherine Turner
ABSTRACT: 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.