BEGIN:VCALENDAR PRODID:-//Columba Systems Ltd//NONSGML CPNG/SpringViewer/ICal Output/3.3- M3//EN VERSION:2.0 CALSCALE:GREGORIAN METHOD:PUBLISH BEGIN:VEVENT DTSTAMP:20151006T150113Z DTSTART:20151012T143000Z DTEND:20151012T153000Z SUMMARY:MCCIR AZ GSK Update Seminar Series UID:{http://www.columbasystems.com/customers/uom/gpp/eventid/}abj-iffhutp u-l71s2e DESCRIPTION:Defining the mechanism(s) that dendritic cells utilise to ini tiate type-2 inflammation\n\nPeter Cook\n\nDendritic cells (DCs) direct CD4+ T cell differentiation into distinct T helper subsets that are vita l for protection against diverse types of infection. However\, the mech anisms employed by DCs to initiate type-2 responses\, which are importan t for immunity to helminth infection as well as being a major contributo r to allergic disease\, remain poorly understood. We have previously de monstrated a crucial role for methyl-CpG-binding domain-2 (Mbd2)\, a pro tein that links DNA methylation to repressive chromatin structure\, in r egulating DC gene expression and ability to promote Th2 immunity in vitr o and in vivo against either helminths or allergens. This revealed a nov el epigenetic mechanism that is integral to DC promotion of CD4+ T cell responses. Several genes were dramatically dysregulated in Mbd2-/- DCs\, identifying potential novel mechanisms that DCs utilise for type-2 prim ing. The chemokine CCL17\, which has been previously been associated wit h recruitment of T cells in type-2 inflammatory settings\, was dramatica lly downregulated in Mbd2-/- DCs. We have found that Ccl17-/- DCs displa y no impairment in type-2 response induction in vitro\, but display seve rely impaired induction of helminth type-2 responses\, and house dust mi te allergic airway inflammation\, following transfer in vivo. This demon strates that DC secretion of CCL17 is vital for optimal priming of type 2 inflammation in vivo. Ongoing work is investigating the role of Mbd2 a nd its downstream gene targets in regulating DC type-2 function in funga l settings. These data identify methyl-CpG-binding proteins and the gene s that they control as potential therapeutic targets for type-2 inflamma tion.\n\n\nDefining the importance of dendritic cell subsets in promotio n and regulation of immunity to Schistosoma mansoni \n\nAlexander Phythi an-adams\n\nAlthough dendritic cells (DCs) are both sufficient and neces sary for induction of Th2 immune responses against Schistosoma mansoni\, the relative contributions of particular DC subsets to this process are poorly understood. CD8?+ cDCs have been shown to play a critical role i n Th1 settings and in cross presentation of bacterial antigens\, but the ir role in Th2 immunity has yet to be addressed. We have used mice that are deficient in the expression of the transcription factor Batf3 (B6-Ba tf3-/-) that lack most CD8?+ lineage cDCs to tackle this question. Batf3 -/- mice injected with S. mansoni eggs displayed dramatically enhanced T h2 cytokine production\, along with increased IL-17 and impaired IFN?\, in comparison to WT controls. Similarly\, S. mansoni infected Batf3-/- e xhibited exaggerated Th2 cytokines and reduced IFN? in the liver and mes enteric lymph nodes. These novel data suggest that CD8?+ cDCs are an int egral part of a mechanism that controls the extent of Th2 responses to e gg antigens. \n\nCulture of murine bone marrow with Flt3-L generates CD2 4hi FLDCs (equivalent to CD8?+ cDCs) and CD11bhi FLDCs (equivalent to CD 11b+ cDCs). To enhance our understanding of the role of CD8?+ and CD11b + cDC subsets in the initiation of adaptive immune responses against S. mansoni\, we sorted CD24hi and CD11bhi FLDCs\, stimulated them overnight with soluble egg Ag (SEA) and transferred them to B6 recipients. Whilst CD24hi cDCs induced the production of only IFN?\, CD11bhi cDCs initiate d a potent Th2 response in recipient mice. Sorted FLDC subsets in co-cul ture with CD4+ T cells promoted cytokine responses that where similarly biased. \n\nAs well as identifying that CD8?+ DCs are dispensable for Th 2 induction against Schistosoma mansoni\, our data support the emerging consensus that CD11b+ conventional DCs are the most effective DC subset at priming Th2 responses in vitro and in vivo.\n STATUS:TENTATIVE TRANSP:TRANSPARENT CLASS:PUBLIC LOCATION:Michael Smith Lecture Theatre\, Michael Smith Building\, Manches ter END:VEVENT END:VCALENDAR