Edwards, Alexander Daniel; (2003) Recognition of microbial patterns by dendritic cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Innate pattern recognition receptors (PRR) for microbes expressed on dendritic cells (DC) link direct recognition of pathogens to initiation of T cell responses. Previously, CD40 triggering had been shown to induce IL-12 production from DC activated by some microbial extracts. I showed that following activation by heat- killed yeasts, murine DC can also make high levels of IL-10 instead of IL-12 when CD40 is triggered. Differential IL-12 or IL-10 production correlated with the class of PRR triggered. Stimulation with mycobacterial components through toll-like receptor (TLR) 2, for example, signalled via MyD88 to condition DC for IL-12 production. In contrast, activation of DC by heat killed yeasts or zymosan particles via a TLR-independent pathway primed for IL-10 production. Importantly, zymosan induced IL-10 via the kinase Syk, and this could be blocked with soluble [beta]-glucans, suggesting that heat-killed yeasts induce IL-10 production via a glucan receptor that signals through immunoreceptor tyrosine-based activation motifs. I investigated cytokine production by phenotypically defined subsets of spleen DC, and demonstrated that microbial stimulation determines cytokine production from individual subsets. For example, CD8[alpha]+ and CD4- CD8[alpha]- subsets can make IL-10 in response to yeasts or IL-12 in response to other stimuli. In spite of this flexibility, there are functional differences between subsets. Thus the CD4+ subset cannot make IL-12 p70 in response to any stimulus. Although many TLR are expressed in all subsets, some are differentially expressed; CD8[alpha]+ express more TLR3, but less TLR5 or TLR7, than the two CD8[alpha]- subsets. Selective absence of TLR7 in CD8[alpha]+ DC correlates with unresponsiveness to the imidazoquinoline R-848. To further characterise differences between DC subsets, I measured gene expression using oligonucleotide microarrays, and identified a number of new subset markers; CD5, CD22 and CD72 are expressed on CD8[alpha]- DC subsets, while CD1d and CD81 are expressed on CD8[alpha]+ DC.

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