Date of Award

2013

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Microbiology and Immunology

Abstract

Regulatory T cells (Tregs) are required for the induction and maintenance of immune homeostasis. Singh et al. demonstrated that depletion of Tregs in mice results in a loss of self-tolerance that manifests in the development of autoimmune diseases such as Inflammatory Bowel Disease (IBD). In humans, autoimmune diseases such as IBD, Multiple Sclerosis (MS), and Type 1 Diabetes are thought to occur due to a deficiency in the number or function of Tregs. The importance of Tregs in modulating the human immune system is perhaps best exemplified by IPEX (immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome), a severe autoimmune disease characterized by a defect in the key Treg transcription factor Foxp3.

Tregs unquestionably play an important role in regulating the immune system, but there is still more to learn about how Tregs are induced. In recent years, vitamin D has been identified as an important immunomodulatory molecule that may promote Treg differentiation.In vitrostudies have confirmed that vitamin D inhibits T cell proliferation and regulates dendritic cell (DC) maturation to promote a tolerogenic phenotype. Moreover, vitamin D deficiency is associated with an increased risk in the development of autoimmune diseases such as MS and Type 1 Diabetes.

Our goal was to test the hypothesis that vitamin D enhances human Treg differentiation and to elucidate the mechanism by which vitamin D modulates immune responses. Here we report that there is a positive correlation between the serum concentration of vitamin D and the Treg frequency in adult peripheral blood. To further study the effect of vitamin D on human Treg differentiation, we used anex vivoculture system to induce Tregs from human umbilical cord blood (UCB). We found that supplementation of vitamin D to human UCB enhanced Treg differentiation. Furthermore, addition of a vitamin D receptor inhibitor to human UCB decreased Treg differentiation. Taken together, these data indicate that vitamin D has a positive effect on human Treg differentiation. Additionally, our data suggest that vitamin D exerts its immunomodulatory effects by acting on monocytes. Vitamin D supplementation enhanced the expression of the monocyte cell surface molecule Neuropilin-1 (NRP-1), which functions to bind TGF-β at the cell surface. TGF-β is an essential immunomodulatory cytokine to induce Tregs in this culture system.

We concluded that vitamin D enhances human Treg differentiation in part by altering the phenotype of monocytes to promote the expression of cell surface molecules important for Treg differentiation. The work encompassed here will contribute to our understanding of vitamin D as an immunomodulatory molecule and potentially aid scientific efforts to develop new therapeutics to treat autoimmune disease.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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