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Role of Interleukin 21 in CD4 T cell regulation

Attridge, Kesley Blair (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

IL-21 is crucial for anti-viral defense, the germinal center reaction and anti-tumour immunity.

Conversely, it has been implicated in various autoimmune conditions, including type-1 diabetes. This study set out to explore how IL-21 influences CD4 T cell immune responses, with particular emphasis on its ability to counteract Treg-mediated suppression. These experiments revealed that IL-21 acted on conventional CD4 T cells to release them from suppression. This was associated with
loss of Treg homeostasis, as IL-21 was able to inhibit IL-2 production and could substitute for IL-2 in conventional but not regulatory T cells.

Analysis of how CD4 T cell responses are controlled was broadened by investigation of the CTLA-4 pathway, a major regulator of T cell immunity. We showed that CTLA-4 could decrease the level of CD86 expression on APCs by trans-endocytosis in vivo, thereby limiting T cell CD28 signalling. In a further development, we showed that IL-21 could directly upregulate CD86 expression by B cells,
illustrating the opposing functions of CTLA-4 and IL-21.
Finally, we explored how the nature of T cell activation influences cytokine production and pathogenicity. These experiments revealed that IL-21 production by CD4 T cells was strongly induced during responses driven by DCs, whilst stimulation with B cells promoted IFNγ expression. Moreover, T cells activated in the presence of DCs were profoundly diabetogenic in an adoptive transfer system, unlike those co-stimulated with B cells. These data provide new insight into the regulation of CD4 T cell responses and how levels of IL-21 produced in vivo could modulate the balance between tolerance and immunity.

Type of Work:Ph.D. thesis.
Supervisor(s):Walker, Lucy
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Immunity and Infection
Subjects:R Medicine (General)
RC Internal medicine
Institution:University of Birmingham
ID Code:3355
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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