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

INTRODUCTIONThe inflammasomes and the complement system are traditionally viewed as quintessential components of innate immunity required for the detection and elimination of pathogens. Assembly of the NLRP3 inflammasome in innate immune cells controls the maturation of interleukin (IL)–1β, a proinflammatory cytokine critical to host defense, whereas activation of the liver-derived complement key components C3 and C5 in serum leads to opsonization and removal of microbes and induction of the inflammatory reaction. Recent studies, however, have highlighted an unanticipated direct role for complement C3 also in human T cell immunity: The anaphylatoxin C3a receptor (C3aR) and the complement regulator CD46 (which binds C3b) are critical checkpoints in human T cell lineage commitment, and they control initiation and resolution of T helper 1 (TH1) responses in an autocrine fashion via T cell–derived and intracellularly activated C3. We explored a novel functional cross-talk of complement with the NLRP3 inflammasome within CD4+ T cells and determined how the cooperation between these two “classically” innate systems directly affects interferon-γ (IFN-γ) production by adaptive immune cells.RATIONALEGiven the critical role of intracellular C3 activation in human TH1 responses and the importance of C5 activation products in inflammation, we investigated whether human CD4+ T cells also harbor an “intracellular C5 activation system” and by what means this system may contribute to effector responses by using C5aR1 and C5aR2 agonists and antagonists, T cells from patients with cryopyrin-associated periodic syndromes (CAPS), and mouse models of infection and autoimmunity.RESULTSHuman CD4+ T cells expressed C5 and generated increased intracellular C5a upon T cell receptor activation and CD46 autocrine costimulation. Subsequent engagement of the intracellular C5aR1 by C5a induced the generation of reactive oxygen species (ROS) and the unexpected assembly of a functional NLRP3 inflammasome in CD4+ T cells, whereas the surface-expressed C5aR2 negatively controlled this process.NLRP3 inflammasome–dependent autocrine IL-1β secretion and activity were required for optimal IFN-γ production by T cells; consequently, dysregulation of NLRP3 function in these cells affected their normal effector responses. For example, mutated, constitutively active NLRP3 in T cells from patients with CAPS induced hyperactive TH1 responses that could be normalized with a NLRP3 inhibitor. The in vivo importance of a T cell–intrinsic NLRP3 inflammasome was further supported by the finding that IFN-γ production by Nlrp3–/– CD4+ T cells was significantly reduced during viral infections in mice and that diminished TH1 induction due to lack of NLRP3 function in a CD4+ T cell transfer model of colitis led to uncontrolled TH17 infiltration and/or expansion in the intestine and aggravated disease.CONCLUSIONOur results demonstrate that the regulated cross-talk between intracellularly activated complement components (the “complosome”) and the NLRP3 inflammasome is fundamental to human TH1 induction and regulation. The finding that established innate immune pathways are also operative in adaptive immune cells and orchestrate immunological responses contributes to our understanding of immunobiology and immune system evolution. In addition, the results suggest that the complement-NLRP3 axis in T cells represents a novel therapeutic target for the modulation of TH1 activity in autoimmunity and infection