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

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

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2222-2234
Number of pages13
JournalJournal of Clinical Investigation
Volume127
Issue number6
DOIs
Publication statusPublished - 2017 Jun 1

ASJC Scopus subject areas

  • Medicine(all)

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    Lan, P., Fan, Y., Zhao, Y., Lou, X., Monsour, H. P., Zhang, X., Choi, Y., Dou, Y., Ishii, N., Ghobrial, R. M., Xiao, X., & Li, X. C. (2017). TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury. Journal of Clinical Investigation, 127(6), 2222-2234. https://doi.org/10.1172/JCI91075