| Literature DB >> 29768177 |
Nicolas Page1, Bogna Klimek1, Mathias De Roo2, Karin Steinbach1, Hadrien Soldati3, Sylvain Lemeille1, Ingrid Wagner1, Mario Kreutzfeldt1, Giovanni Di Liberto1, Ilena Vincenti1, Thomas Lingner4, Gabriela Salinas4, Wolfgang Brück5, Mikael Simons6, Rabih Murr7, Jonathan Kaye8, Dietmar Zehn9, Daniel D Pinschewer10, Doron Merkler11.
Abstract
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.Entities:
Keywords: Listeria monocytogenes; T cell differentiation; autoimmunity; cytotoxic T cells; experimental autoimmune encephalomyelitis; lymphocytic choriomeningitis virus; multiple sclerosis; thymocyte selection-associated high-mobility group box factor; transcription factor
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Year: 2018 PMID： 29768177 PMCID： PMC6040915 DOI： 10.1016/j.immuni.2018.04.005
Source DB: PubMed Journal: Immunity ISSN： 1074-7613 Impact factor: 31.745