Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH

Abstract

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The Extracellular ATP Receptor P2RX7 Imprints a Promemory Transcriptional Signature in Effector CD8+ T Cells

“…One example is eATP, which can be released actively through exporting channels, such as pannexin-1 (43,44), or passively by dying cells due to local or systemic inflammation and tissue damage (23). One eATP sensor in particular (P2RX7) is expressed at high levels and plays relevant roles in controlling CD8 1 T cell responses (24,25,45,46). Because eATP can be released actively or passively, it is possible that CD8 1 T cells are exposed to this signal not only at sites of active viral infection but also in secondary lymphoid organs during initial effector function.…”

Hepatic Stellate Cell-Immune Interactions in NASH

“…Metabolic derangement in NASH also induces T cell pathology. Notably, CXCR6 + CD8 + T cells acquire hepatocyte killing activity in response to increased levels of the short-chain fatty acid acetate ( 136 ). Accordingly, depletion of T lymphocyte populations or disruption of their signaling activity is protective ( 115 , 133 , 137 ).…”

Regulation of Progression and Resolution of Liver Fibrosis by Immune Cells

“…The scar-associated macrophage identified by Ramachandran et al has also been suggested to be of bone marrow origin. 30 34 Therefore, it is becoming evident that bone marrow–derived macrophages exhibit a pathogenic phenotype in NASH pathology.…”

“…More recently, the details of CD8 T cells in a CD-HFD-induced NASH model have been investigated. 34 CD8 T cells that accumulate in the liver in NASH have a liver-resident phenotype of CXC chemokine receptor (CXCR) 6+ and are tissue resident memory (Trm)-like cells that are maintained and activated by IL-15. This led to the new concept that human and mouse CD8 Trm-like cells acquire an autoaggressive phenotype that exerts cytotoxic activity independently of MHC class I via acetate and ATP-P2 × 7 signaling.…”

“…• CXCR6 + CD8 T cells promote CDHF diet-fibrosis via attacking hepatocyte MHC class I independently 34…”