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.
Author Info: (1) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (2) Center for Infectious Medicine, Department of Medicine Huddinge,
Author Info: (1) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (2) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (3) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (5) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (6) Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. (7) Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. (8) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (9) Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. (10) Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. (11) Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. (12) Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. (13) Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. (14) Department of Applied Physics, Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden. Department of Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden. (15) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (16) IrsiCaixa AIDS Research Institute, Badalona, Spain. Universitat de Vic-Universitat Central de Catalunya, Vic, Spain. Institucio Catalana de Recerca i Estudis Avancats, ICREA, Barcelona, Spain. (17) Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. (18) Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. (19) Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. (20) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (21) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. marcus.buggert@ki.se.
