Toll Like Receptor Dependent Control of T Helper 17 Cell Differentiation and Inflammasome Activation
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Activation of pattern recognition receptors on dendritic cells (DCs) and macrophages leads to secretion of cytokines that control activation and differentiation of CD4+ T cells. While IL-12 is critical for Th1 lineage development, IL-6 and TGF-b play an important role in differentiation of Th17 cells in vitro. IL-1 has also been implicated in regulating Th17 differentiation. In this dissertation, we examined the relative contribution of IL-6 and IL-1 for in vivo Th17 differentiation, and found that requirements for Th17 polarization depend entirely on the site of priming. While IL-6 plays a critical role in Th17 lineage priming in the skin and the mucosal tissue such as the gut and the lung, it is completely dispensable for Th17 priming in the spleen. IL-1R signaling in T cells is however necessary for Th17 priming in all tissues. Moreover, the differential cytokine requirements for Th17 lineage commitment are guided by differential population of DCs resident in different tissues. These results reveal fundamental differences by which the systemic, mucosal, and cutaneous immune systems guide Th17 cell lineage commitment. Pathogenic infections and tissue injuries trigger the assembly of inflammasomes, cytosolic protein complexes that activate caspase-1 leading to cleavage of pro-IL-1β/pro-IL-18, and pyroptosis, a pro-inflammatory cell death program. Although microbial recognition by Toll-like receptors (TLR) induces synthesis of pro-IL-1β and pro-IL-18, its role in inflammasome activation is insufficiently understood. In this dissertation, we have discovered that simultaneous activation of TLRs and NLRP3, which likely mimics natural infection by pathogenic microbes, triggers rapid caspase-1 cleavage, release of alarmins and pyroptosis. This acute caspase-1 activation is independent of new protein synthesis and depends on the TLR signaling molecule IRAK-1 and its kinase activity. Importantly, Listeria monocytogenes induces NLRP3-dependent rapid caspase-1 activation and pyroptosis, both of which depend on IRAK-1. These results demonstrate that simultaneous sensing of microbial ligands and virulence factors by TLRs and NLRP3 respectively leads to a rapid TLR- and IRAK-1-dependent assembly of the NLRP3 inflammasome, and such activation is important for release of alarmins, pyroptosis, and early IFN-γ production by memory T cells, all of which could be critical for early host defense.