The NLRP3 inflammasome controls interleukin-1beta 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-1beta secretion, thereby promoting interferon-gamma 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.
- Arbore, G.
- West, E. E.
- Spolski, R.
- Robertson, A. A. B.
- Klos, A.
- Rheinheimer, C.
- Dutow, P.
- Woodruff, T. M.
- Yu, Z. X.
- O'Neill, L. A.
- Coll, R. C.
- Sher, A.
- Leonard, W. J.
- Kohl, J.
- Monk, P.
- Cooper, M. A.
- Arno, M.
- Afzali, B.
- Lachmann, H. J.
- Cope, A. P.
- Mayer-Barber, K. D.
- Kemper, C.
Keywords
- Adaptive Immunity
- Animals
- Autocrine Communication
- CD4-Positive T-Lymphocytes/*immunology
- Carrier Proteins/genetics/*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/antagonists & inhibitors/metabolism
- Receptors, Antigen, T-Cell/agonists/metabolism
- Receptors, Chemokine/agonists/antagonists & inhibitors/metabolism
- Th1 Cells/*immunology
