Control of T cell interleukin 21 production in a mouse model of type-1 diabetes

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Wardzinski, Lukasz (2014). Control of T cell interleukin 21 production in a mouse model of type-1 diabetes. University of Birmingham. Ph.D.

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Abstract

IL-21 is a potent immune modulator crucial for the generation of protective anti-viral and humoral responses. Nonetheless, the detrimental effects of IL-21 are well documented in a variety of autoimmune diseases including type-1 diabetes. Although elevated IL-21 mRNA expression has been reported in mouse models of diabetes, it remained unclear which cells are responsible for its production and whether this cytokine was expressed by cells that infiltrate the pancreas. We addressed these questions by evaluating IL-21 production in the DO11xRIP-mOVA mouse model of type-1 diabetes. Our findings demonstrated that conventional CD4 T cells are the main source of IL-21 protein and T cell expression of this cytokine was markedly enriched within the pancreas, suggesting a potential role at the site of the autoimmune attack.

Since both dendritic cells and B cells are abundant within the pancreatic lesion, we explored the capacity of these cells to contribute to T cell IL-21 production. Our investigation revealed that bone marrow-derived dendritic cells are constitutively able to support T cell IL-21 production, whereas B cell stimulated cultures required additional stimuli such as the provision of exogenous IL-6. Interestingly, our study identified a novel CD25+ innate lymphoid cell population in the pancreas, which appears to be a counterpart of the innate lymphoid cell populations recently described in the gut and lungs. Pancreas-derived CD4-CD25+ innate lymphoid cells could promote T cell IL-21 production in vitro, raising the possibility that this population contributes to T cell IL-21 production within the autoimmune lesion.

Collectively, these data suggest that IL-21 production is a characteristic feature of pancreas-specific CD4 T cell responses. A better understanding of how this cytokine is elicited and how it contributes to autoimmune pathology is likely to be valuable for future therapeutic interventions.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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