T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4⁺ T cells.
The NLRP3 inflammasome controls interleukin-1β maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described. We found that the NLRP3 inflammasome assembles in human CD4(+) T cells and initiates caspase-1-dependent interleukin-1β secretion, thereby promoting interferon-γ production and T helper 1 (T(H)1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2. Aberrant NLRP3 activity in T cells affects inflammatory responses in human autoinflammatory disease and in mouse models of inflammation and infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to "innate immune cells" but is an integral component of normal adaptive T(H)1 responses.
MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.
Giuseppina
G
Arbore
Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Erin E
EE
West
Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Rosanne
R
Spolski
Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, QLD 4072, Australia.
Avril A B
AAB
Robertson
Institute for Medical Microbiology and Hospital Epidemiology, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Andreas
A
Klos
Institute for Medical Microbiology and Hospital Epidemiology, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Claudia
C
Rheinheimer
Institute for Medical Microbiology and Hospital Epidemiology, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Pavel
P
Dutow
Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, QLD 4072, Australia.
Trent M
TM
Woodruff
Pathology Core, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Zu Xi
ZX
Yu
School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
Luke A
LA
O'Neill
Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, QLD 4072, Australia.
Rebecca C
RC
Coll
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Alan
A
Sher
Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Warren J
WJ
Leonard
Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.|Division of Immunobiology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Jörg
J
Köhl
Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, UK.
Pete
P
Monk
Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, QLD 4072, Australia.
Matthew A
MA
Cooper
Genomics Centre, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, UK.
Matthew
M
Arno
MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.|Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
Behdad
B
Afzali
UK National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Campus, London NW3 2PF, UK.
Helen J
HJ
Lachmann
Academic Department of Rheumatology, Division of Immunology, Infection and Inflammatory Diseases, King's College London, London SE1 1UL, UK.
Andrew P
AP
Cope
Laboratory of Clinical Infectious Diseases, Inflammation and Innate Immunity Unit, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Katrin D
KD
Mayer-Barber
MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.|Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Claudia
C
Kemper
D056704:Adaptive Immunity; D000818:Animals; D019898:Autocrine Communication; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003167:Complement Activation; D015936:Complement C5a / Q000276:immunology*; D056587:Cryopyrin-Associated Periodic Syndromes / Q000276:immunology; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D051916:Membrane Cofactor Protein / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000378:metabolism; D019707:Receptors, Chemokine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*
C488033:C5AR1 protein, human; C417003:C5aR2 protein, human; C497857:CD46 protein, human; D002352:Carrier Proteins; D058847:Inflammasomes; D051916:Membrane Cofactor Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; D044087:Receptor, Anaphylatoxin C5a; D011948:Receptors, Antigen, T-Cell; D019707:Receptors, Chemokine; D015936:Complement C5a; D007371:Interferon-gamma