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

Details

Serval ID
serval:BIB_00D136C4113F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection.
Journal
Nature
Author(s)
Alfei F., Kanev K., Hofmann M., Wu M., Ghoneim H.E., Roelli P., Utzschneider D.T., von Hoesslin M., Cullen J.G., Fan Y., Eisenberg V., Wohlleber D., Steiger K., Merkler D., Delorenzi M., Knolle P.A., Cohen C.J., Thimme R., Youngblood B., Zehn D.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
07/2019
Peer-reviewed
Oui
Volume
571
Number
7764
Pages
265-269
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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 potential <sup>1-4</sup> . This process, known as T cell exhaustion or dysfunction <sup>1</sup> , 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) <sup>5-8</sup> . The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood <sup>9-12</sup> . 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) protein <sup>13-15</sup> . 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 <sup>+</sup> 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.
Keywords
Animals, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/pathology, Cell Proliferation, Chronic Disease, Cytokines/immunology, Cytokines/metabolism, Epigenesis, Genetic, Female, Gene Expression Regulation/immunology, Hepacivirus/immunology, Hepatitis C, Chronic/immunology, Hepatitis C, Chronic/virology, Hepatocyte Nuclear Factor 1-alpha/metabolism, High Mobility Group Proteins/metabolism, Homeodomain Proteins/metabolism, Humans, Immunologic Memory, Lymphocytic Choriomeningitis/immunology, Lymphocytic Choriomeningitis/virology, Lymphocytic choriomeningitis virus/immunology, Male, Mice, Phenotype, Thymocytes/cytology, Thymocytes/immunology, Transcription, Genetic
Pubmed
Web of science
Create date
19/08/2019 12:47
Last modification date
03/10/2019 6:09
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