Journal Article

TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury

Ghobrial, Rafik M., Zhao, Yue, Lou, Xiaohua, Li, Xian Chang, Xiao, Xiang, Lan, Peixiang, Zhang, Xiaolong, Ishii, Naoto, Fan, Yihui, Monsour, Howard P., Choi, Yongwon, Dou, Yaling

2017

Overview

Tissue-resident immune cells play a key role in local and systemic immune responses. The liver, in particular, hosts a large number of invariant natural killer T (iNKT) cells, which are involved in diverse immune responses. However, the mechanisms that regulate survival and homeostasis of liver iNKT cells are poorly defined. Here we have found that liver iNKT cells constitutively express the costimulatory TNF superfamily receptor OX40 and that OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the release of potent proinflammatory cytokines that induce liver injury. This OX40/NKT pyroptosis pathway also plays a key role in concanavalin A-induced murine hepatitis. Mechanistically, we demonstrated that liver iNKT cells express high levels of caspase 1 and that OX40 stimulation activates caspase 1 via TNF receptor-associated factor 6-mediated recruitment of the paracaspase MALT1. We also found that activation of caspase 1 in iNKT cells results in processing of pro-IL-1β to mature IL-1β as well as cleavage of the pyroptotic protein gasdermin D, which generates a membrane pore-forming fragment to produce pyroptotic cell death. Thus, our study has identified OX40 as a death receptor for iNKT cells and uncovered a molecular mechanism of pyroptotic cell death. These findings may have important clinical implications in the development of OX40-directed therapies.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Apoptosis / Arthritis / Autoimmune diseases / Biomedical research / Caspase / Caspase 1 - metabolism / Caspase-1 / Caspases - metabolism / Cell death / Cell Line / Chemical and Drug Induced Liver Injury - metabolism / Chemical and Drug Induced Liver Injury - pathology / Concanavalin A / Cytokines / Enzyme Activation / Genetic aspects / Genetic variation / Health aspects / Hepatitis / Hepatocytes / Homeostasis / IL-1β / Immune response / Inflammation / Ligands / Liver diseases / Lymphocytes / Male / Mice, Inbred C57BL / Mice, Knockout / Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / Natural killer cells / Natural Killer T-Cells - physiology / Neoplasm Proteins - metabolism / Paracaspases / Protein Transport / Pyroptosis / Receptors, OX40 - physiology / Roles / T cell receptors / Tumor necrosis factor / Tumor necrosis factor receptors / Viral infections