Journal
SCIENCE IMMUNOLOGY
Volume 5, Issue 49, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aba7918
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Funding
- Swedish Research Council (VR)
- Karolinska Institutet
- Swedish Society for Medical Research (SSMF)
- Jeansson Stiftelser
- Ake Wibergs Stiftelse
- Swedish Society of Medicine
- Cancerfonden
- Barncancerfonden
- Magnus Bergvalls Stiftelse
- Hedlunds Stiftelse
- Lars Hiertas Stiftelse
- Swedish Physician against AIDS Foundation
- Jonas Soderquist Stiftelse
- Clas Groschinskys Minnesfond
- NIH [P01-AI131568, AI076066, AI118694, AI106481]
- Penn Center for AIDS Research [AI045008]
- European Union's Horizon 2020 research and innovation program [681137-EAVI2020]
- Welcome Trust [100326/Z/12/Z]
- Wellcome Trust [100326/Z/12/Z] Funding Source: researchfish
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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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