T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes.
Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process. 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 1beta 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.
Guarda
Greta
G
Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
Dostert
Catherine
C
Staehli
Francesco
F
Cabalzar
Katrin
K
Castillo
Rosa
R
Tardivel
Aubry
A
Schneider
Pascal
P
Tschopp
Jürg
J
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D007113:Immunity, Innate / Q000276:immunology*; D007156:Immunologic Memory; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000276:immunology; D008024:Ligands; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009504:Neutrophils / Q000276:immunology; D010529:Peritoneal Cavity / Q000166:cytology; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D053583:Interleukin-1beta; D008024:Ligands; C529636:NALP1 protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D048069:Tumor Necrosis Factors; D020170:Caspase 1