Immune modulation by parasitic nematodes
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Date
2009Author
Grainger, John Robert
Metadata
Abstract
Almost 2 billion people world-wide are infected with parasitic helminths. These
complex multicellular eukaryotic organisms are capable of establishing long-term
infections even in the face of an intact immune response. Typically, in these settings
regulatory components of the immune response, such as Foxp3+ T regulatory cells
(Tregs), become dominant, limiting protective effector responses towards the
parasite. Helminths are thought to have evolved mechanisms, including release of
immunomodulatory molecules termed excretory-secretory products (ES), to sway the
balance between the regulatory and effector arms of the immune response to favour
their persistence. In this thesis both the development of a protective immune
response toward, and the potential manipulation of the immune response by, the
rodent gastrointestinal nematode Heligmosomoides polygyrus have been studied.
Firstly, the effects of H. polygyrus ES (HES) on bone-marrow derived
dendritic cells (DCs) were analysed. Although HES did not alter the phenotype of the
DC it was found to be able to suppress the ability of the DC to respond to
inflammatory stimuli. This activity was lost when HES was heat-inactivated
(hiHES). After adoptive transfer, HES-pulsed DCs were able to induce a HESspecific
T helper (Th)2-type response even if co-treated with an inflammatory
stimulus. Th2-type responses are protective against H. polygyrus infection.
Surprisingly, the ability of HES to generate a Th2-response in a co-treatment
situation was not related to its anti-inflammatory properties; DCs co-treated with
hiHES and an inflammatory stimulus were able to drive an equivalent Th2-response
to HES in this situation.
Next, making use of mouse strains with different susceptibility phenotypes to
primary H. polygyrus infection, potential mechanisms of resistance were
characterised. Development of granulomas in the gut wall were found to be
associated with reduced worm burdens. Furthermore, in highly susceptible C57BL/6
mice, production of IL-23 was shown to be counter-regulatory to this process, as
mice on the same background but deficient in this cytokine have increased numbers
of granulomas and dramatically enhanced resistance. Susceptibility to H. polygyrus
was also considered at the level of epigenetic regulation. A protein that binds
specifically to methylated DNA, methyl-CpG binding domain protein (MBD)2, was
found to affect the proportion of Foxp3+ Tregs within the CD4+ T cell population in
vivo. Additionally, in vitro induction of Foxp3 in response to TGF-β was enhanced
in MBD2-/- CD4+ T cells. MBD2-/- mice had a trend towards increased worm burdens
when infected with H. polygyrus, suggesting that the difference in proportion of
Tregs may limit generation of an effector response.
Finally, the ability of HES to directly affect the regulatory arm of the immune
response was focussed upon. It was found that HES was able to induce Foxp3
expression in naïve peripheral T cells, and that this was mediated by stimulation of
the TGF-β pathway. The TGF-β mimic was of parasite origin as a pan-vertebrate
TGF-β antibody was unable to block its effects but sera from H. polygyrus infected
animals was competent to do this. Activity of this type was not limited to HES as ES
from the ovine helminth Haemonchus contortus was found to have the same
property. These data imply that some helminth parasites have evolved mechanisms to
support generation of Foxp3+ Tregs, thus favouring the regulatory arm of the
immune response and hence their own persistence.