Abstract

Parasites have evolved effective mechanisms to manipulate an immune response and prevent expulsion from the host. Most notably, some gut helminths can also downregulate T cell responses to inflammatory stimuli including asthmatic and allergic reactions through stimulation and expansion of Foxp3+ regulatory T cells. Experiments in our lab have shown that Foxp3+ regulatory T cell expansion in vitro can be linked to a TGF -beta-like activity present in the excretory/secretory products of the rodent gut helminth Heligmosomoides Polygyrus. Chronic persistence of the adult worm infection can be modified by use of a synthetic TGF -beta type 1 receptor inhibitor in vivo.

I am interested in the mechanisms underlying this Foxp3+ regulatory T cell expansion in vivo and have focused on whether antigen presenting cells such as dendritic cells are re-programmed to a tolerogenic, regulatory T cell inducing, phenotype following infection. I have found that chronic helminth infection is associated with the expansion of CD11c(lo) dendritic cells in the draining lymph nodes of the gut. These cells have a plasmacytoid dendritic cell phenotype, a distinct response to TLR ligation and present antigen to T cells far less efficiently on comparison to conventional CD11c(hi) dendritic cells. CD11c(lo) cells polarise naive T cells to distinct T cells lineages, encouraging the expansion of antigen-specific Foxp3 T cells and polarisation away from Th17 cells. These regulatory T cell changes could be inhibited with excess antigen or the retinoic acid receptor antagonist LE540 and are enhanced with recombinant TGF -beta. My research is now focusing on manipulating plasmacytoid dendritic cell populations in vivo and determining the cause for the changes in the CDllc(lo) and Foxp3+ T cell populations following infection. Ultimately, my interest is in understanding the immunological mechanisms underlying helminth persistence, to determine whether these conditions can be replicated to drive tolerance in vivo.