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TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection
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Journal Article
TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection
2019
Overview
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
1
–
4
. This process, known as T cell exhaustion or dysfunction
1
, 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 understood
9
–
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) protein
13
–
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.
TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infections.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/31
/ 13/44
/ 13/51
/ 14/34
/ 14/35
/ 38
/ 38/109
/ 38/39
/ 38/91
/ Animals
/ Antigens
/ CD8-Positive T-Lymphocytes - immunology
/ CD8-Positive T-Lymphocytes - pathology
/ Cloning
/ DNA
/ Female
/ Gene Expression Regulation - immunology
/ Genomes
/ Hepatitis C, Chronic - immunology
/ Hepatitis C, Chronic - virology
/ Hepatocyte Nuclear Factor 1-alpha - metabolism
/ High mobility group proteins
/ High Mobility Group Proteins - metabolism
/ Homeodomain Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Immunity
/ Letter
/ Lymphocytic Choriomeningitis - immunology
/ Lymphocytic Choriomeningitis - virology
/ Lymphocytic choriomeningitis virus - immunology
/ Male
/ Melanoma
/ Mice
/ mRNA
/ Proteins
/ Science
/ T cells
/ Tumors
/ Viruses
