Innate instruction of adaptive immunity revisited: the inflammasome

Abstract

The innate immune system regulates initial responses to pathogen invasion through a set of conserved pattern recognition receptors (PRR). The best-characterized PRRs are the Toll-like receptors, which regulate not only the initial pathogen defense response, but also adaptive immune responses. Thus, insight into the function of PRRs has major implications for our understanding of the physiology of vaccination and the pathophysiology of human disease. Recent advances in our understanding of a new class of pattern recognition receptors--NOD-like receptors (NLR)--have similarly provided insight into both innate and adaptive immunity. In particular, the NLR Nlrp3 (also known as Nalp3 or Cias1) forms an intracellular multimolecular complex with active caspase-1, called an inflammasome, creating a platform for regulating secretion of interleukin-1 (IL-1) family members. Given the important role of IL-1 in inflammatory diseases, from gout to rheumatoid arthritis, the importance of understanding the regulation of such a cytokine cannot be underestimated. In this review, we address new evidence supporting a role for adaptive immune activation by recently identified NLR agonists, with a particular focus on Nlrp3. Basic questions in our understanding of Nlrp3 inflammasome activation are also presented.

Figure 1. Proposed model of adaptive immune system activation by inflammasome stimulation with the adjuvant aluminium hydroxide

Alum and antigen are phagocytosed by an APC and, through an unknown mechanism, activate the Nlrp3 inflammasome, resulting in secretion of the pro-inflammatory cytokines IL-1β, IL-18 and IL-33 and potentially other immune modulatory molecules. In conjunction with antigen recognition on the APC by the T-cell receptor (TCR), IL-1 receptor (IL-1R) stimulation (or another inflammasome-dependent signal) provides ‘signal 2’ for CD4⁺ T-cell priming, the first step in generation of adaptive immunity.