The mechanisms by which the recognition of Toll-like receptor (TLR) ligands leads to host immunity remain poorly defined. It is now thought that to induce an effective immune response, microorganisms must stimulate complex sets of pattern-recognition receptors, both within and outside of the TLR family. The combined activation of these different receptors can result in complementary, synergistic or antagonistic effects that modulate innate and adaptive immunity. Therefore, a complete understanding of the role of TLRs in host resistance to infection requires 'decoding'of these multiple receptor interactions. Our past work has uncovered the significant synergy in dendritic cell activation between ligands of different T cell receptors and the role of type I interferon in regulating TLR downstream signaling in both dendritic cells and tissue and tumor cells. In particular we showed that the cellular response to TLR ligands is not only production of pro-inflammatory mediators but they are also involved in control of tissue homeostasis and regulate cellular differentiation, proliferation, and apoptosis. The balance between MyD88 and TRIF signaling and the production of type I IFN determine proliferation versus apoptosis in tissue and tumor cells and activation versus survival in dendritic cells. We also have found that the stimulation of the dendritic cells by betaglucan (a component of yeast and fungi) through the dectin 1 receptor facilitate the induction of an Th17 response in human and synergize with TLR receptor stimulation for activation of dendritic cells and pro-inflammatory cytokine production. In the last year we have discovered that the signaling through dectin 1, a receptor with an ITAM-like motif in its cytoplasmic portion, results in the induction of only a small number of early responding cytokine such as Il-1beta, Il-6, and TNF and in only a very modest activation of NF-kappaB. However, IL-1beta induced by beta-glucan stimulation (and processed through the inflammasome also activated through dectin-1 stimulation) exert a potent positive feedback mechanisms that it is necessary for optimal NF-kappaB activation and production of late responsive cytokines such as IL-12 and IL-23. We now plan to extend the study of the IL-1 family of cytokines in the activation of dendritic cells and other immune cells by ITAM-containing receptors. In particular we want to understand how much the ability of these receptors to activate NF-kappaB is direct through BCL10 activation or it is dependent through the amplifying signal provided by endogenous IL-1. We also want to understand the molecular mechanisms by which different ITAM-containing receptors positively or negatively regulate the responsiveness of dendritic cells and myeloid cells to TLR ligands. In particular we want to undersatnd the role of the Akt/mTOR pathway and its modulation by type I interferon. Dendritic cells, macrophages, and other myeloid cells play a role both in the regulation of the adaptive and innate immune response to infection as well as in the regulation and dysregulation of inflammation as it relates to infections, degenerative and autoimmune diseases and cancer. Regulating through these mechanisms dendritic cell and myeloid cell functions is important in the planning of immunotherapy (e.g. vaccine, cancer immunotherapy) as well in targeting inflammation-based pathology in disease therapy and cancer prevention/treatment.
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