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Title: Differential roles for dendritic cell subsets during Schistosoma mansoni infection
Author: Marley, Angela Kerstin
ISNI:       0000 0004 6063 0266
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2015
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Schistosoma mansoni infection leads to chronic inflammation and detrimental granulomatous pathology mediated largely by Th2 immune responses. Dendritic cells (DCs) provide an essential link between the innate and the adaptive immune response, and are critical for Th2 induction during S. mansoni infection. But the function of DCs in this process and the specific mechanisms they employ are not yet fully understood. Indeed, the role for individual DC subsets during the induction of Th2 responses is also unclear. Furthermore, the importance of DCs during the formation of granulomatous legions, and whether they interact with T cells at this site, is yet to be determined. The formation of granulomatous pathology is initiated by the onset of S. mansoni egg production, as eggs get stuck in the intestine and the liver. In the first part of this thesis the formation of granulomas in the liver during S. mansoni infection is studied. Novel methods for quantification of histological data are used to examine the kinetics of granuloma development and the location of CD11c+ DCs throughout infection. Additionally, CD11c-diphtheria toxin receptor mice are used to investigate the importance of DCs during granuloma formation. Depletion of CD11c+ DCs resulted in a striking reduction in granuloma formation at the time-point for initial egg arrival in the liver. Two weeks later, depletion of CD11c+ DCs did not impede granuloma formation, however led to altered structural arrangement of the granuloma. These data highlight the importance of DCs during the initial granuloma formation process, so as to prevent the toxic damage to hepatocytes by the S. mansoni egg. DC subsets display unique functions in infection settings. The function of CD8α+ cDCs during the induction of Th1 responses is well understood, however their role during Th2 induction is yet to be determined. In the second part of this thesis the importance of one of these subsets, CD8α+ cDCs, during Th2 induction is assessed using Batf3-/- mice. Lacking CD8α+ cDCs and migratory CD103+ cDCs, Batf3-/- mice displayed dysregulated induction of immune responses during S. mansoni infection. This altered the immunological balance to an enhanced Th2 and impaired Th1 response ultimately leading to fatality of Batf3-/- mice. This underlines that CD8α+ cDCs are not fundamentally required for the induction of Th2 immune responses, yet they play a role either directly or indirectly for the induction of appropriate immune responses during S. mansoni infection. As implied DCs are capable of inducing very strong Th2 immune responses, however S. mansoni does not classically activate DCs. To elucidate further, the expression of activation markers is muted in response to SEA compared to bacterial or viral stimuli. In the final part of this thesis a co-culture system is used to address whether S. mansoni infection alters the function of DCs in the liver during infection. More specifically, the ability of DCs to take up, process and present antigen to CD4+ T cells and thereby induce T cell proliferation and cytokine production was assessed. Comparing cDCs to pDCs revealed that cDC are more efficient inducers of CD4+ T cell responses, however no major changes were found after S. mansoni infection. In contrast, co-culture with specific DC subsets illuminated that only CD8α− cDCs have enhanced capabilities to induce CD4+ T cell responses during S. mansoni infection. These data demonstrate that distinct DC subsets may hold the key for unravelling the mechanisms for Th2 induction.
Supervisor: Maizels, Rick ; MacDonald, Andrew Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: immunology ; parasitology