NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8⁺ T cells.
Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-γ (IFN-γ) secretion by noncognate memory CD8(+) T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8α(+) DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL-18) and IL-1β, only IL-18 was required for IFN-γ production by memory CD8(+) T cells. Conversely, only the release of IL-1β, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity.
Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia.
Andreas
A
Kupz
Greta
G
Guarda
Thomas
T
Gebhardt
Leif E
LE
Sander
Kirsty R
KR
Short
Dimitri A
DA
Diavatopoulos
Odilia L C
OL
Wijburg
Hanwei
H
Cao
Jason C
JC
Waithman
Weisan
W
Chen
Daniel
D
Fernandez-Ruiz
Paul G
PG
Whitney
William R
WR
Heath
Roy
R
Curtiss
Jürg
J
Tschopp
Richard A
RA
Strugnell
Sammy
S
Bedoui
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002135:Calcium-Binding Proteins / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005408:Flagellin / Q000276:immunology; D007156:Immunologic Memory; D058847:Inflammasomes / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011552:Pseudomonas Infections / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D012481:Salmonella Infections, Animal / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology; D015012:Yersinia pseudotuberculosis Infections / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D051193:Toll-Like Receptors; D005408:Flagellin; D007371:Interferon-gamma