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T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes

Abstract

Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process1. The inflammatory response must be actively terminated, however, because failure to do so can result in ‘bystander’ damage to tissues and diseases such as arthritis or type-2 diabetes. Yet the mechanisms controlling excessive inflammatory responses are still poorly understood. Here we show that mouse effector and memory CD4+ T cells abolish macrophage inflammasome-mediated caspase-1 activation and subsequent interleukin 1β release in a cognate manner. Inflammasome inhibition is observed for all tested NLRP1 (commonly called NALP1) and NLRP3 (NALP3 or cryopyrin) activators, whereas NLRC4 (IPAF) inflammasome function and release of other inflammatory mediators such as CXCL2, interleukin 6 and tumour necrosis factor are not affected. Suppression of the NLRP3 inflammasome requires cell-to-cell contact and can be mimicked by macrophage stimulation with selected ligands of the tumour necrosis factor family, such as CD40L (also known as CD40LG). In a NLRP3-dependent peritonitis model, effector CD4+ T cells are responsible for decreasing neutrophil recruitment in an antigen-dependent manner. Our findings reveal an unexpected mechanism of inflammasome inhibition, whereby effector and memory T cells suppress potentially damaging inflammation, yet leave the primary inflammatory response, crucial for the onset of immunity, intact.

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Figure 1: Memory and effector T cells inhibit the BMDM NLRP3 inflammasome in an antigen-dependent manner.
Figure 2: T cells selectively inhibit NLRP3 and NLRP1 inflammasomes.
Figure 3: TNF family ligands expressed by T cells inhibit the NLRP3 inflammasome.
Figure 4: Neutrophil recruitment to the peritoneum is suppressed in mice with effector T cells.

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Acknowledgements

We thank H. Acha-Orbea, P. Launois, E. Luescher, H. R. MacDonald, P. Romero, M. Kopf and R. Flavell for knockout and transgenic mice; H. Acha-Orbea and M. Eckert for critical reading and comments; A. Yazdi for discussions; and M. Braun and D. Labes for technical help. This work was in part supported by the Swiss National Science foundation and the NCCR Molecular Oncology. C.D. is supported by an EMBO long-term fellowship.

Author Contributions G.G. performed and designed the experiments and wrote the paper. C.D., F.S., K.C., R.C. and A.T. contributed to performing the experiments. P.S. provided the TNF ligand reagents and discussed the data throughout the experimental phase. J.T. designed and discussed the experiments and supervised the project.

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Correspondence to Jürg Tschopp.

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Guarda, G., Dostert, C., Staehli, F. et al. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature 460, 269–273 (2009). https://doi.org/10.1038/nature08100

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