Maizels, Rick

McSorley, Henry

2009-10-29T09:11:56Z

2009-10-29T09:11:56Z

2008

Many helminth parasites are able to survive for long periods in immunocompetent hosts. It has been suggested that the successful establishment of helminths is in part due to the induction of regulatory T cells (Tregs) which suppress anti-parasite immune responses. A possible mechanism by which parasites induce Tregs would be production of TGF-β, which can induce immunosuppressive Treg cells and also directly suppress immune responses. TGF-β homologues have been identified in parasitic nematodes including Brugia malayi, Schistosoma mansoni and Ancylostoma caninum. The B. malayi TGF-β homologue, Bm-TGH-2, has been demonstrated to signal through the mammalian TGF-β receptor, which indicates the TGF-β homologues may have a function in the host. We hypothesised that Treg induction through parasite-derived TGF-β could be a potent method by which parasites could evade the host immune system. To address this, molecular techniques were first used to identify and characterise the transcription of novel TGF-β homologues from the intestinal parasites Haemonchus contortus, Heligmosomoides polygyrus, Nippostrongylus brasiliensis and Teladorsagia circumcincta, showing that TGF-β homologues are present in a wide range of parasites. TGF-β activity was then shown in products from both S. mansoni and H. polygyrus, and indeed the H. polygyrus products were found to induce Tregs through the TGF-β pathway. Antiserum against bacterially expressed H. polygyrus TGF-β homologue (Hp-TGH-2) was produced, and used to probe H. polygyrus excretory/secretory products, showing that Hp-TGH-2 is secreted. Attempts were also made to express recombinant Bm-TGH-2 (B. malayi TGF-β homologue) in insect cells, however the purified protein proved not to be functional. - v - In vivo mouse models of B. malayi infection were tested to examine the phenotype of T cell responses at the site of infection. An accumulation was found of CD4+Foxp3+CD25+CTLA-4hiCD103+ T cells, which resemble activated natural Tregs, and which were suppressive in vitro. This proportion of Tregs at the site of infection diminishes over time, however CD103 expression (which is associated with activated Tregs) is increased on Tregs present at all timepoints up to day 21 postinfection, indicating that although a growing effector response may outgrow Tregs over time, the Treg population remains activated. Using an adoptive transfer model, it was shown that the Treg induction could spread to other bystander responses. In IL-4R-deficient mice, Treg accumulation was unaffected, indicating alternatively activated macrophages (which are absent in these mice) are not required for Treg induction.

http://hdl.handle.net/1842/3157

en

The University of Edinburgh

Biological Sciences

Immunology

TGF-β homologues from parasites: inducers of immune regulation?

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy