Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Recent outbreaks in vertically transmitted viruses, such as Zika virus and HIV, have rejuvenated interest in fetal and neonatal immune tolerance. Babies are susceptible to vertically transmitted viruses because fetal and neonatal immune systems are considered to be immune-privileged and will tolerate antigens presented to them by their mother. Thus, understanding the mechanisms of this tolerance is important to design effective treatments for infected mothers to protect their offspring. Here, I define a novel Treg, a type of T cell that mediates tolerance, named bidirectional T cells (BiT), found in human umbilical cord blood (UCB). These cells are induced by monocytes that provide transforming growth factor-beta (TGF-β), a necessary molecule for Treg induction. BiT express classical Treg markers, such as Foxp3 and CD25, but also produce proinflammatory cytokines such as GM-CSF and IL-8. This profile suggests that BiT are capable of suppressing and activating the immune system. These differences suggest that BiTs may function differently from in vitro induced Tregs (iTregs), peripheral in vivo induced Tregs (pTregs) and thymus derived Tregs (tTregs).Our lab has been able to show that physiological levels of calcitriol, the active form of vitamin D, is able to upregulate the induction of BiT. Furthermore, we also discovered that calcitriol upregulates NRP-1, a receptor and activator of TGF-β, on monocytes. We decided to further determine the effect of calcitriol on T cells and monocytes to better understand its role in immune suppression. We found that calcitriol promoted the expression of molecules that turn off the immune system, CTLA-4 and PD-L1, on T cells. The NRP-1 expression on these monocytes was upregulated, which lead to increased migration of cells. The migration towards VEGF signifies what happens after tissue damage or during the growth of new blood vessels. In summary, we describe a novel Treg (BiT) and found that calcitriol promoted immune suppression by upregulating BiT, molecules that turn off the immune system, and IFN-β impeded the migration of cells to areas that require growth.

Creative Commons License

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

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