TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury
Peixiang Lan, … , Xiang Xiao, Xian Chang Li
Peixiang Lan, … , Xiang Xiao, Xian Chang Li
Published April 24, 2017
Citation Information: J Clin Invest. 2017;127(6):2222-2234. https://doi.org/10.1172/JCI91075.
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Research Article Immunology Inflammation

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

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.

Authors

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

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Figure 1

OX40 stimulation readily depletes iNKT cells in vivo.

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OX40 stimulation readily depletes iNKT cells in vivo. (A) Cell surface e...
(A) Cell surface expression of OX40 by iNKT, NK, T, and B cells and CD11b+ cells from the liver of naive WT B6 mice was analyzed by FACS. Data shown are from one of 3 independent experiments. (B) Mononuclear cells in the liver of WT B6, OX40L-Tg, and Ox40-KO mice were isolated, and iNKT cells were identified by CD1d-αGalCer and CD3 staining and analyzed by FACS. The gate shows iNKT cells, as well as the relative percentage among total cells retrieved. The FACS plots shown represent one of 6 individual experiments. (C) The summary bar graphs represent relative percentage and absolute number of iNKT cells in the liver of WT B6, OX40L-Tg, and Ox40-KO mice. The data shown are mean ± SD of 6 experiments. (D) The FACS plot shows the relative percentage of iNKT cells in the liver of WT B6 mice 2 weeks after treatment with OX86, anti-OX40L mAb, or a control (Ctrl) IgG (200 μg, i.p.). The plot shown represents one of 6 individual experiments. (E) The summary graphs show relative percentage and absolute number of iNKT cells from the liver of WT B6 mice treated with OX86, anti-OX40L mAb, or control IgG. Data shown are mean ± SD of 6 experiments. (F) WT B6 mice were treated with OX86 or control IgG (200 μg, i.p.), and iNKT cells in the host spleen, thymus, bone marrow (BM), and lymph nodes (LN) were determined using CD1d-αGalCer and anti-CD3 staining, gated, and analyzed by FACS. Data shown represent one of 3 individual experiments. (G) FACS-sorted iNKT cells from the liver of DsRed mice were transferred into WT B6 or OX40L-Tg hosts (1 × 106 cells per mouse). The presence of DsRed iNKT cells in the liver of host mice was determined by FACS. Data shown represent one of 3 independent experiments. P values were calculated using 1-way ANOVA (C and E), *P < 0.05.