TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection

Francesca Alfei, Kristiyan Kanev, Maike Hofmann, Ming Wu, Hazem E. Ghoneim, Patrick Roelli, Daniel T. Utzschneider, Madlaina von Hoesslin, Jolie G. Cullen, Yiping Fan, Vasyl Eisenberg, Dirk Wohlleber, Katja Steiger, Doron Merkler, Mauro Delorenzi, Percy A. Knolle, Cyrille J. Cohen, Robert Thimme (), Benjamin Youngblood () and Dietmar Zehn ()
Additional contact information
Francesca Alfei: Technical University of Munich
Kristiyan Kanev: Technical University of Munich
Maike Hofmann: University of Freiburg
Ming Wu: Technical University of Munich
Hazem E. Ghoneim: St Jude Children’s Research Hospital
Patrick Roelli: Technical University of Munich
Daniel T. Utzschneider: The University of Melbourne
Madlaina von Hoesslin: Technical University of Munich
Jolie G. Cullen: Technical University of Munich
Yiping Fan: St Jude Children’s Research Hospital
Vasyl Eisenberg: Bar-Ilan University
Dirk Wohlleber: Technical University of Munich
Katja Steiger: Technical University of Munich
Doron Merkler: University of Geneva
Mauro Delorenzi: University of Lausanne
Percy A. Knolle: Technical University of Munich
Cyrille J. Cohen: Bar-Ilan University
Robert Thimme: University of Freiburg
Benjamin Youngblood: St Jude Children’s Research Hospital
Dietmar Zehn: Technical University of Munich

Nature, 2019, vol. 571, issue 7764, 265-269

Abstract: Abstract Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential1–4. This process, known as T cell exhaustion or dysfunction1, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)5–8. The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood9–12. Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein13–15. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1+ self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.

Date: 2019
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DOI: 10.1038/s41586-019-1326-9

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