NLRP1 and NLRP3 in T and NK cell immunity

NOD-like receptor family pyrin domain containing-1 and -3 proteins (NLRP1 and NLRP3) are important components of macromolecular complexes called inflammasomes. Inflammasome activation induces caspase-1-mediated cleavage and activation of pro-IL-1ß and pro-IL-18. NLRP1 is expressed in natural killer (NK), T, and myeloid cells, and is significantly involved in the pathogenicity of anthrax lethal toxin. However, its functional role in these immune cells is still poorly understood. In contrast, NLRP3 is primarily expressed in myeloid cells and activated by a variety of signals. NLRP3 hyperactivation is associated with pathological processes, such as autoimmune and inflammatory diseases but also carcinogenesis and tumor progression. The role of NLRP3 apart from its function in the inflammasome has not been investigated yet. Remarkably, Nlrp3-deficient mice are more resistant to tumor metastasis through a mechanism that involves altered myeloid differentiation and enhanced NK cell recruitment. Hitherto the mechanistic details of this effect have not been studied. Additionally, it was suggested that NLRP3 might have an impact on Th1/Th2 cell polarization under specific experimental conditions, which is independent of its well-established function in the inflammasome complex. In this project I aim to study the relevance of NLRP3 (i) in T cell differentiation, T cell priming by antigen-presenting cells and the generation of T cell effector functions and (ii) in NK cell survival and chemotaxis. The second part of the project addresses the question, whether NLRP1 shares a similar function with NLRP3 in the fight against bacterial infections and tumor development. This work will give new insights in the role of NOD-like receptors in the development of innate and adaptive immune cell responses.

NOD-like receptor family pyrin domain containing proteins (NLRP) are important components of macromolecular complexes called inflammasomes, which are responsible for the production and release of the pro-inflammatory cytokines IL-1ß and IL-18. In this project I aimed to study the impact of NLRP1 on antitumor immunity. In collaboration with Prof. Mark J. Smyth and Dr Kyohei Nakamura (QIMR Berghofer Medical Research Institute, Brisbane, Australia), we uncovered that NLRP1 has an important role in multiple myeloma (cancer of plasma cells). Loss of NLRP1 or inhibition of IL-18 significantly protects from myeloma progression. IL-18 induces the generation of myeloid-derived suppressor cells, which potently dampen the antitumor function of CD8+ T lymphocytes. These results suggest that IL-18 could be a potential therapeutic target to overcome immunosuppression in multiple myeloma. In addition, I planned to investigate the function of NLRP3 in T lymphocytes, as we hypothesized that NLRP3 might have an impact on T helper cell polarization. However, shortly after joining the QIMR Berghofer Medical Research Institute two competing laboratories reported the role of NLRP3 in the differentiation of TH2 cells. Although this development was certainly not desirable, it corroborated my original hypothesis and gave me the opportunity to work on other projects. In collaboration with the laboratories of Dr. Nicholson and Dr. Huntington (Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia) we elucidated the molecular details of the negative regulation of IL-15 signaling in NK cells. We identified cytokine-inducible SH2- containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Deletion of Cish in gene-modified mice renders NK cells hypersensitive to IL-15 leading to enhanced NK cell proliferation, survival, IFN- production and cytotoxicity towards tumors. This data uncovered CIS as a potent intracellular checkpoint in NK cell- mediated antitumor immunity. Further, I investigated the role of heparanase in NK cell migration and tumor surveillance. It is well-known that NK cells are highly efficient at preventing cancer metastasis but are infrequently found in the core of primary tumors. We uncovered that NK cell invasion of primary tumors and recruitment to the site of metastasis are strictly dependent on the presence of heparanase. Our study suggests that maintaining and/or enhancing heparanase expression in NK cells will improve NK cell-based anticancer immunotherapy.