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

• Published in: Nature (London) 2019-07, Vol.571 (7764), p.265-269
• Main Authors: Alfei, Francesca, Kanev, Kristiyan, Hofmann, Maike, Wu, Ming, Ghoneim, Hazem E., Roelli, Patrick, Utzschneider, Daniel T., von Hoesslin, Madlaina, Cullen, Jolie G., Fan, Yiping, Eisenberg, Vasyl, Wohlleber, Dirk, Steiger, Katja, Merkler, Doron, Delorenzi, Mauro, Knolle, Percy A., Cohen, Cyrille J., Thimme, Robert, Youngblood, Benjamin, Zehn, Dietmar
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 13/44; 13/51; 14/34; 14/35; 38; 38/109; 38/39; 38/91; 631/250/2152/1566/1571; 631/250/2152/1566/1618; Animals; Antigens; Bioinformatics; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell death; Cell Proliferation; Chronic Disease; Chronic infection; Clonal deletion; Cloning; Cytokines; Cytokines - immunology; Cytokines - metabolism; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA methylation; Effector cells; Epigenesis, Genetic; Exhaustion; Female; Gene expression; Gene Expression Regulation - immunology; Gene regulation; Genetic aspects; Genomes; Genotype & phenotype; Hepacivirus - immunology; Hepatitis; Hepatitis C; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - virology; Hepatocyte nuclear factor 1; Hepatocyte Nuclear Factor 1-alpha - metabolism; High mobility group proteins; High Mobility Group Proteins - metabolism; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Humans; Immunity; Immunologic Memory; Immunotherapy; Infections; Letter; Lymphocytes; Lymphocytes T; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - virology; Lymphocytic choriomeningitis virus - immunology; Male; Melanoma; Mice; Molecular modelling; mRNA; multidisciplinary; PD-1 protein; Phenotype; Phenotypes; Physiological aspects; Proteins; Receptors; Science; Science (multidisciplinary); Skin cancer; T cell receptors; T cells; Thymocytes - cytology; Thymocytes - immunology; Transcription, Genetic; Tumors; Viral infections; Virus diseases; Viruses
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1326-9

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.