Role of Interleukin 21 in CD4 T cell regulation

Attridge, Kesley Blair (2012). Role of Interleukin 21 in CD4 T cell regulation. University of Birmingham. Ph.D.

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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:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):