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Phenotypic and functional characterization of T cells and Foxp3⁺ T regulatory cells in inflammatory bowel disease : steps towards T regulatory cell therapy in mucosal disease

University of British Columbia

Because of their potent suppressive capacity and critical role in the normal function of the human immune system, T regulatory cells (Tregs) have long been considered candidates for the therapeutic treatment of autoimmune and chronic inflammatory diseases. However, the clinical implementation of these cells has proven challenging in practice, in part due to a lack of knowledge surrounding this T cell subset. Specifically, an evaluation of the unique functions of individual Treg cell lineages, along with a comprehensive investigation of the non-suppressive capacities of these cells, including chemokine production, is necessary. Furthermore, in the application of Treg cellular therapy in mucosal diseases such as inflammatory bowel disease, the identification of putative antigens that can be targeted by Tregs is warranted. To these aims, I evaluated the phenotypic and functional characteristics of Helios⁺ and Helios⁻ Treg subsets, with the knowledge that expression of Helios, an Ikaros family transcription factor, may differentiate natural, thymic derived Tregs from their in vivo peripherally induced counterparts. I found that Helios positive and negative Treg subsets expressed similar Treg markers and displayed a similar capacity for suppression and plasticity. However, these Tregs did differ in terms of cytokine/chemokine production as well as methylation state of the FOXP3 Treg-specific demethylated region. Futhermore, total populations of FOXP3⁺ Tregs were evaluated for chemokine expression; I found that Tregs produce significant quantities of CXCL8 and other acute phase chemokines, and are able to attract inflammatory cells of the innate immune system. In addition, FOXP3 expression enhances CXCL8 production, likely because of its ability to bind the CXCL8 gene promoter. To evaluate putative antigens that can be targeted by Treg therapy in inflammatory bowel disease, I assessed the role of flagellin in disease. Flagellin exacerbates colitic disease in mice in a TLR5 independent manner and flagellin-specific T cells can be identified in patients with CD. Collectively, these findings bring us closer to the effective application of Treg cellular therapy in the setting of mucosal disease.

Text

2012-06-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/42517

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/