Project Summary The innate immune system has several families of pattern recognition receptors to detect invading pathogens and initiate inflammatory responses to rapidly eliminate the pathogen. The innate immune system also plays an instructive role in induction of adaptive immune responses against virulent pathogens. Toll-like receptors (TLR) are one such family of receptors and their activation in cells of the innate immune system, such as dendritic cells and macrophages, induces secretion of several pro-inflammatory cytokines such as IL-6, IL-12, TNFα, etc. Many of these cytokines play an important role in T cell activation and differentiation. TLR activation also leads to synthesis of a second family of cytokines comprised of IL-1 and IL-18 which are cleaved into active forms and secreted following activation of a different family of cytosolic receptors called NOD like receptors (NLRs). The cytokines IL-1 and IL-18 have major influence in directing T cell activation and differentiation and more importantly use the same signaling components as the TLR signaling pathway. It is becoming clear that IL-1 and IL-18 are the major players in innate control of adaptive immunity and the mechanisms by which they regulate T cell activation and differentiation are not completely understood. Our previous work has shown that IL-R mediated MyD88 dependent signaling is critical for Th17 lineage differentiation in systemic and mucosal immune systems. Th17 cells are crucial for fighting fungal and extracellular bacterial infections and have also been implicating in causing auto-immune diseases such as Rheumatoid Arthritis and Inflammatory Bowel Disease. It is therefore crucial to understand the cellular and molecular mechanisms by which these cells are regulated. In our new studies we have found that IL-1 plays a critical role in regulating effector functions of already primed Th17 memory T cells. We propose to build on these findings and gain a deeper understanding of how IL-1 regulates functioning of Th17 cells and elucidate the physiological significance of IL-1 mediated regulation of Th17 effector functions. In Aim 1, we will understand of the cellular and molecular mechanisms by which IL-1 is made during dendritic cell-memory Th17 cell interactions. In Aim 2, we will elucidate the signaling and molecular mechanisms by which IL-1R signaling in T cells impacts production of IL-17 and related family of cytokines. In Aim 3, we will use in vivo approaches to understand the importance of IL-1R signaling in memory Th17 cell function and examine the role of IL-1 in reactivation of pathogen specific memory Th17 cells as well as memory Th17 cells that cause auto-immunity . These studies will significantly advance our understanding of the role of IL-1 family of cytokines in regulation of CD4 T cell functions. Further more, unraveling the molecular mechanisms by which IL-1 family of cytokines regulate effector and memory T cell functions will not only enhance our und...