Cytokine signals and immune competition in the Th2 response to helminth infection

Webster, Holly Christine (2021) Cytokine signals and immune competition in the Th2 response to helminth infection. PhD thesis, University of Glasgow.

Abstract

Type 2 immunity is activated in response to both allergens and helminths, but it can be detrimental or beneficial depending on the stimuli. These conflicting outcomes highlight the importance of understanding the regulation of this response. Th2 cells are key for the clearance of helminth infections in the SILP. IL-10 is a regulatory cytokine that is highly expressed during human and murine helminth infection, but its role in helminth infection remains unclear. The aim of this thesis is to assess if IL-10 acts directly or indirectly to promote the type 2 immune response while also suppressing counter-active Th1 cells which provide immune competition.
We show that helminth infection results in increased IL-10 expression in both the SILP and the draining MLN in mice, with highest expression in the infected tissue. In vivo blockade of IL-10 led to a significant decrease in IL-13, IL-5 and GATA3 expression by Th2 cells in the intestine and not in the MLN. In vitro, IL-10 induced expression of GATA3 and production of IL-5 and IL-13 in purified CD4+ T cells. The impact of IL-10 was partially dependent on IFNγ signalling, and in vivo, surface IL-10 receptor expression was higher on Th1 cells than on Th2 cells and highest on Th1 cells in the SILP. Due to the nature of the H. polygyrus lifecycle, where at two-time points worms move through the wall of the intestine. We hypothesised that a possible indirect mechanism for IL-10 promotion of Th2 cells was via suppression of IFNγ responses as a result of bacteria stimuli. However, our data show no major disruption to the intestinal barrier during infection. Although, we do report IFNγ responses in the SILP, MLN and omentum over the course of H. polygyrus infection. Suggesting IFNγ may play multiple roles during infection. Furthermore, we found that MLN cells from H. polygyrus infected mice produced IFNγ when stimulated with HES, suggesting that IFNγ responses towards H. polygyrus itself may occur, although the function of this in the immune response to H. polygyrus remains unclear.
Understanding immune competition during H. polygyrus infection contributes towards the understanding of the immune response to helminths and with further work may contribute towards treatment strategies. In addition, IL-10 optimisation of Th2 responses during helminth infection may be applied to the treatment of helminth infections and other type 2 mediated diseases.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Helmith infection, cytokine regulation, T cells, mucosal immunology.
• Subjects: Q Science > Q Science (General); Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Supervisor's Name: Perona-Wright, Dr. Georgia and Maizels, Professor Rick
• Date of Award: 2021
• Depositing User: Miss Holly Christine Webster
• Unique ID: glathesis:2021-82221
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 May 2021 11:47
• Last Modified: 27 May 2021 11:55
• Thesis DOI: 10.5525/gla.thesis.82221
• URI: https://theses.gla.ac.uk/id/eprint/82221