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

Sekine, Takuya, Perez-Potti, André, Nguyen, Son, Gorin, Jean-Baptiste, Wu, Vincent H., Gostick, Emma, Llewellyn-Lacey, Sian, Hammer, Quirin, Falck-Jones, Sara, Vangeti, Sindhu, Yu, Meng, Smed-Sörensen, Anna, Gaballa, Ahmed, Uhlin, Michael, Sandberg, Johan K., Brander, Christian, Nowak, Piotr, Goepfert, Paul A., Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Betts, Michael R. and Buggert, Marcus 2020. TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Science Immunology 5 (49) , eaba7918. 10.1126/sciimmunol.aba7918

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association for the Advancement of Science
ISSN:	2470-9468
Date of First Compliant Deposit:	15 July 2020
Date of Acceptance:	22 June 2020
Last Modified:	06 Nov 2023 15:29
URI:	https://orca.cardiff.ac.uk/id/eprint/133455

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