MCCIR AZ GSK Update Seminar Series
|Starts:||15:30 12 Oct 2015|
|Ends:||16:30 12 Oct 2015|
|What is it:||Seminar|
|Organiser:||Faculty of Life Sciences|
|Who is it for:||University staff, Adults, Current University students|
|Speaker:||Alexander Phythian-adams, Peter Cook|
Defining the mechanism(s) that dendritic cells utilise to initiate type-2 inflammation
Dendritic cells (DCs) direct CD4+ T cell differentiation into distinct T helper subsets that are vital for protection against diverse types of infection. However, the mechanisms employed by DCs to initiate type-2 responses, which are important for immunity to helminth infection as well as being a major contributor to allergic disease, remain poorly understood. We have previously demonstrated a crucial role for methyl-CpG-binding domain-2 (Mbd2), a protein that links DNA methylation to repressive chromatin structure, in regulating DC gene expression and ability to promote Th2 immunity in vitro and in vivo against either helminths or allergens. This revealed a novel 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 priming. The chemokine CCL17, which has been previously been associated with recruitment of T cells in type-2 inflammatory settings, was dramatically downregulated in Mbd2-/- DCs. We have found that Ccl17-/- DCs display no impairment in type-2 response induction in vitro, but display severely impaired induction of helminth type-2 responses, and house dust mite allergic airway inflammation, following transfer in vivo. This demonstrates that DC secretion of CCL17 is vital for optimal priming of type 2 inflammation in vivo. Ongoing work is investigating the role of Mbd2 and its downstream gene targets in regulating DC type-2 function in fungal settings. These data identify methyl-CpG-binding proteins and the genes that they control as potential therapeutic targets for type-2 inflammation.
Defining the importance of dendritic cell subsets in promotion and regulation of immunity to Schistosoma mansoni
Although dendritic cells (DCs) are both sufficient and necessary 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 in Th1 settings and in cross presentation of bacterial antigens, but their 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-Batf3-/-) that lack most CD8?+ lineage cDCs to tackle this question. Batf3-/- mice injected with S. mansoni eggs displayed dramatically enhanced Th2 cytokine production, along with increased IL-17 and impaired IFN?, in comparison to WT controls. Similarly, S. mansoni infected Batf3-/- exhibited exaggerated Th2 cytokines and reduced IFN? in the liver and mesenteric lymph nodes. These novel data suggest that CD8?+ cDCs are an integral part of a mechanism that controls the extent of Th2 responses to egg antigens.
Culture of murine bone marrow with Flt3-L generates CD24hi FLDCs (equivalent to CD8?+ cDCs) and CD11bhi FLDCs (equivalent to CD11b+ 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 initiated a potent Th2 response in recipient mice. Sorted FLDC subsets in co-culture with CD4+ T cells promoted cytokine responses that where similarly biased.
As well as identifying that CD8?+ DCs are dispensable for Th2 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.
Travel and Contact Information
Michael Smith Lecture Theatre
Michael Smith Building