T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4⁺ T cells

Giuseppina Arbore; Erin E West; Rosanne Spolski; Avril A B Robertson; Andreas Klos; Claudia Rheinheimer; Pavel Dutow; Trent M Woodruff; Zu Xi Yu; Luke A O'Neill; Rebecca C Coll; Alan Sher; Warren J Leonard; Jörg Köhl; Pete Monk; Matthew A Cooper; Matthew Arno; Behdad Afzali; Helen J Lachmann; Andrew P Cope; Katrin D Mayer-Barber; Claudia Kemper

doi:10.1126/science.aad1210

T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4⁺ T cells

Science. 2016 Jun 17;352(6292):aad1210. doi: 10.1126/science.aad1210.

Authors

Giuseppina Arbore^#¹, Erin E West^#², Rosanne Spolski², Avril A B Robertson³, Andreas Klos⁴, Claudia Rheinheimer⁴, Pavel Dutow⁴, Trent M Woodruff³, Zu Xi Yu⁵, Luke A O'Neill⁶, Rebecca C Coll³, Alan Sher⁷, Warren J Leonard², Jörg Köhl^{8

9}, Pete Monk¹⁰, Matthew A Cooper³, Matthew Arno¹¹, Behdad Afzali^{1

12}, Helen J Lachmann¹³, Andrew P Cope¹⁴, Katrin D Mayer-Barber¹⁵, Claudia Kemper^{1

2}

Affiliations

¹ MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, London SE1 9RT, UK.
² Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
³ Institute for Molecular Bioscience and School of Biomedical Sciences, University of Queensland, QLD 4072, Australia.
⁴ Institute for Medical Microbiology and Hospital Epidemiology, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
⁵ Pathology Core, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
⁶ School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
⁷ Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
⁸ Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
⁹ Division of Immunobiology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA.
¹⁰ Department of Infection and Immunity, University of Sheffield, Sheffield S10 2RX, UK.
¹¹ Genomics Centre, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, UK.
¹² Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
¹³ UK National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Campus, London NW3 2PF, UK.
¹⁴ Academic Department of Rheumatology, Division of Immunology, Infection and Inflammatory Diseases, King's College London, London SE1 1UL, UK.
¹⁵ Laboratory of Clinical Infectious Diseases, Inflammation and Innate Immunity Unit, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity
Animals
Autocrine Communication
CD4-Positive T-Lymphocytes / immunology*
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Complement Activation
Complement C5a / immunology*
Cryopyrin-Associated Periodic Syndromes / immunology
Disease Models, Animal
HEK293 Cells
Humans
Immunity, Innate
Inflammasomes / immunology*
Inflammation / immunology
Interferon-gamma / biosynthesis*
Membrane Cofactor Protein / immunology
Mice
Mice, Mutant Strains
NLR Family, Pyrin Domain-Containing 3 Protein
Reactive Oxygen Species / metabolism
Receptor, Anaphylatoxin C5a / agonists
Receptor, Anaphylatoxin C5a / antagonists & inhibitors
Receptor, Anaphylatoxin C5a / metabolism
Receptors, Antigen, T-Cell / agonists
Receptors, Antigen, T-Cell / metabolism
Receptors, Chemokine / agonists
Receptors, Chemokine / antagonists & inhibitors
Receptors, Chemokine / metabolism
Th1 Cells / immunology*

Substances

C5AR1 protein, human
C5aR2 protein, human
CD46 protein, human
Carrier Proteins
Inflammasomes
Membrane Cofactor Protein
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
Reactive Oxygen Species
Receptor, Anaphylatoxin C5a
Receptors, Antigen, T-Cell
Receptors, Chemokine
Complement C5a
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding