Uncovering a novel role for Duoxa2 in NK cell development
File(s)
Author(s)
Mc Intyre, Stacey
Type
Thesis
Abstract
The DUOX2/DUOXA2 system is involved in the generation of hydrogen peroxide. In the thyroid, hydrogen peroxide produced by DUOX2/DUOXA2 is essential for thyroid hormone synthesis. Consequently, mutations in DUOX2 and DUOXA2 result in congenital hypothyroidism. Recently, Duoxa2-/- mice were found to be extremely susceptible to pulmonary colonisation when subjected to an experimental metastasis assay. Duoxa2-/- mice were also found to exhibit a perturbation of immune homeostasis, with defects in several immune populations, including NK cells. However, this complex is not known to play a direct role in the immune system. Therefore, this PhD investigated the mechanism by which DUOXA2 is involved in immunoregulation, focusing on NK cells. It was found that Duoxa2-/- mice exhibit a severe defect in NK cells. Mature NK cells were significantly reduced and an accumulation of refined-NKPs was evident in the bone marrow. Together these results indicate a defect in NK cell maturation in the absence of DUOXA2.
Importantly, Duoxa2-/- mice are congenitally hypothyroid. Thyroid hormones have been demonstrated to influence various immune cells, including NK cells. They have been shown to increase NK cell cytotoxicity, but NK cells from hyperthyroid patients also have reduced cytotoxic capacity. However, evidence for the relationship between thyroid hormones and the immune system remains limited. Interestingly, induction of hypothyroidism in mice using a low-iodine 0.15% Propothiouracil diet resulted in a similar NK cell defect to that observed in Duoxa2-/- mice. Hypothyroid mice also exhibited a reduction of mature NK cells and a build-up of refined-NKPs, suggesting that hypothyroidism is driving this phenotype. Signalling through thyroid receptors can regulate gene expression and is essential for normal neurodevelopment. Therefore, thyroid hormones may also regulate gene expression during NK cell development. In summary, these results identify a novel and fundamental role for thyroid hormone in the regulation of NK cell development in mice.
Importantly, Duoxa2-/- mice are congenitally hypothyroid. Thyroid hormones have been demonstrated to influence various immune cells, including NK cells. They have been shown to increase NK cell cytotoxicity, but NK cells from hyperthyroid patients also have reduced cytotoxic capacity. However, evidence for the relationship between thyroid hormones and the immune system remains limited. Interestingly, induction of hypothyroidism in mice using a low-iodine 0.15% Propothiouracil diet resulted in a similar NK cell defect to that observed in Duoxa2-/- mice. Hypothyroid mice also exhibited a reduction of mature NK cells and a build-up of refined-NKPs, suggesting that hypothyroidism is driving this phenotype. Signalling through thyroid receptors can regulate gene expression and is essential for normal neurodevelopment. Therefore, thyroid hormones may also regulate gene expression during NK cell development. In summary, these results identify a novel and fundamental role for thyroid hormone in the regulation of NK cell development in mice.
Version
Open Access
Date Issued
2023-07-26
Date Awarded
2024-02-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Thomas, David
Denton, Alice
Publisher Department
Department of Immunology and Inflammation
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)