CD46-mediated signals in the regulation of T-cell cytokine production and intestinal wound healing

Complement is a key part of innate immunity and vital in the first line of defence against invading pathogens. The understanding of the role of complement in the host’s immune defence has undergone its first major change when it became clear that complement is also required for the optimal induction and function of adaptive immunity, particularly B cell activation and T cell effector responses. It is now also becoming increasingly clear that complement plays a key role in the contraction of T cell responses and thus, by definition, in immune homeostasis. The first part of this thesis focuses on such least understood role of complement. Firstly, evidence is reported for a novel mechanism by which the complement regulatory protein CD46 regulates the key T helper type 1 cytokine IFN-y and the canonical immunosuppressive cytokine IL-10. The production of both IFN-y and IL-10 is shown to be temporally regulated by TCR and CD46 signals in CD4+ T cells in an IL-2-dependent fashion and is shown to be defective in rheumatoid arthritis patients. The molecular pathways linked to the CD46-induced switch of TR! cells are largely undefined and were investigated. Gene array studies highlighted the asparagine endopeptidase (AEP) as a candidate molecule involved in the regulation of the switch of TH1 cells towards IL-10 production. The CD46-driven IFN-y secretion, but not the intracellular expression, was found to be substantially reduced by AEP inhibition; IL-10 production was consequently affected confirming the importance of IFN-y signalling in the CD46-induced "switch" mechanism. The cytokines produced by T cells activated via CD46 may also be important in the crosstalk with surrounding tissues. Here the functional consequences of CD46 signals were further investigated in the context of intestinal epithelial cells to allow the discrimination of the effects of CD46 signals in the two different cells types.<br/>A novel role for CD46 in the promotion of cellular proliferation and wound healing was reported.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2012

Author dc:creator

• Cardone, John

Advisors dc:contributor.advisor

• Kemper, Claudia
• Sacks, Steven Howard

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/4b3dcd9c-8cfa-4fe4-80fc-2bda8ef31bfe

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/4b3dcd9c-8cfa-4fe4-80fc-2bda8ef31bfe