Inflammasome-dependent IL-1β production is critical for complete Freund’s adjuvant-induced helper T cell polarization (136.44)

Abstract

Abstract The innate immune system recognizes pathogens/antigens via several families of pattern recognition receptors (PRRs). Often, several PRRs will be triggered, resulting in an innate immune response via a complex integration of signals. However, the importance of different PRR signaling pathways in determining adaptive responses such as helper T cell polarization is not fully understood. We studied the role of two pathways—TLRs and the inflammasome—in promoting helper T cell polarization in response to complete Freund’s adjuvant (CFA). Mice immunized with ovalbumin (OVA) in CFA developed an OVA-specific Th1/Th17 response that was dependent on the signaling adaptor MyD88. TLRs were only partially required for this response, whereas interleukin 1 (IL-1) receptor signaling and the inflammasome were critical. We found that heat-killed M. tuberculosis H37Ra, a component of CFA, induces mature IL-1β production in vitro in a process that requires potassium efflux and reactive oxygen species and is mediated by the NLRP3 receptor. We further showed that the major inflammasome-triggering component of H37Ra is the peptidoglycan. However, the peptidoglycan-sensing receptors NOD1 and NOD2 were not needed for this response. Our data suggest that NOD1/2-independent recognition of mycobacterial peptidoglycan by the NLRP3 inflammasome induces IL-1β production and may play an important role in CFA-induced helper T cell responses. This work was supported by the NIAID Intramural Research Program.