Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells

• DOI: 10.1016/j.immuni.2018.04.005
• Publication Date: 2018-05-15T14:51:16Z
• Authors: Nicolas Page; Bogna Klimek; Mathias De Roo; Karin Steinbach; Hadrien Soldati; Sylvain Lemeille; Ingrid Wagner; Mario Kreutzfeldt; Giovanni Di Liberto; Ilena Vincenti; Thomas Lingner; Gabriela Salinas; Wolfgang Brück; Mikael Simons; Rabih Murr; Jonathan Kaye; Dietmar Zehn; Daniel D. Pinschewer; Doron Merkler
• Keywords: Adult; Male; 0301 basic medicine; immunology [T-Lymphocytes, Cytotoxic]; metabolism [CD8-Positive T-Lymphocytes]; info:eu-repo/classification/ddc/616.07; virology [CD8-Positive T-Lymphocytes]; genetics [Homeodomain Proteins]; immunology [Autoimmunity]; Autoimmunity; ddc:616.07; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; immunology [Signaling Lymphocytic Activation Molecule Family]; 03 medical and health sciences; ddc:590; Signaling Lymphocytic Activation Molecule Family; metabolism [Homeodomain Proteins]; info:eu-repo/classification/ddc/617; physiology [Lymphocytic choriomeningitis virus]; Animals; Humans; Lymphocytic choriomeningitis virus; ddc:576.5; ddc:610; Aged; Homeodomain Proteins; Mice, Knockout; 0303 health sciences; virology [Lymphocytic Choriomeningitis]; immunology [Lymphocytic choriomeningitis virus]; ddc:617; info:eu-repo/classification/ddc/576.5; info:eu-repo/classification/ddc/590; immunology [CD8-Positive T-Lymphocytes]; Rhox8 protein, mouse; info:eu-repo/classification/ddc/616.8; Middle Aged; immunology [Lymphocytic Choriomeningitis]; Cd244a protein, mouse; ddc:616.8; 3. Good health; Mice, Inbred C57BL; immunology [Homeodomain Proteins]; Female; T-Lymphocytes, Cytotoxic

Infections are thought to trigger CD8+ cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue-destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection. TOX repressed the activity of several transcription factors (including Id2, TCF-1, and Notch) that are known to drive CTL differentiation. TOX also reduced immune checkpoint sensitivity by restraining the expression of the inhibitory checkpoint receptor CD244 on the surface of CTLs, leading to increased CTL-mediated damage in the CNS. Our results identify TOX as a transcriptional regulator of tissue-destructive CTLs in autoimmunity, offering a potential mechanistic link to microbial triggers.