Slack, E.M.C.; (2006) Regulation of dendritic cell function by Dectin-1. Doctoral thesis , University of London.

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Abstract

Innate pattern recognition receptors (PRRs) expressed on dendritic cells (DC) link direct recognition of pathogens to initiation of T cell responses. Here I describe evidence that Dectin-1 is a novel pattern recognition receptor involved the activation of dendritic cells by the yeast cell wall preparation, zymosan. Zymosan contains ligands for the known PRR Toll-like Receptor-2 (TLR2). Interestingly, recent work in macrophages has implicated the p-glucan receptor Dectin-1 in zymosan recognition. This thesis demonstrates that Dectin-1 can function as a PRR independently of the Toll-like Receptor system to induce DC cytokine production (IL-2, IL-10) and Notch-ligand upregulation (Jagged-1). My work has helped determine that Dectin-1 can signal via a novel HemlTAM motif to the tyrosine kinase Syk. DC stimulated with zymosan upregulate IL-10, IL-2 and Jagged-1 in a Syk-dependent manner. Indeed, IL-10 and Jagged-1 induction is independent of TLR-mediated recognition of zymosan. In addition, zymosan induced ERK activation is entirely dependent on signalling through Syk and is independent of TLR signalling. I demonstrate that this ERK activation is necessary for the induction of IL-2 and IL-10 in response to zymosan. Finally I present preliminary findings on how the unusual cytokine signature of zymosan-stimulated DCs may bias Thl and Thl7 differentiation induced in vitro.

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