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
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
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