Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

It is known that the elderly are more susceptible to illnesses and infections and respond poorly to immunization. A contributing factor to a decrease in the immune response in the elderly is the decline in the production of naïve T cell by the thymus. In the thymus, the notch receptor expressed on early T cell progenitors (ETP) binds to its ligand expressed on thymic epithelial cells (TEC), signaling ETP to develop through a series of developmental stages before maturing into naive T cells. Because ETP are non-self renewing, the thymus relies on the bone marrow (BM) for a continuous supply of T cell progenitors to generate and maintain the peripheral T cell pool. With age, the numbers of TEC, ETP, as well as the number of T cell progenitors in the BM are reduced, contributing to the decline in the production of naïve T cells. Previously, our lab has shown that with age, the decline in the number of thymocytes correlates with the decline in the expression of Foxn1 in thymic stroma. Foxn1 is a transcription factor critical for functional maturation of TEC and thymic organogenesis. Mutations in Foxn1 result in the nude phenotype characterized by hairless and athymic conditions. Interestingly, nude mice also have defects in the BM, suggesting a role for Foxn1 in hematopoiesis. A Foxn1Tg mouse model was developed in which Foxn1 is over expressed in thymus and in the BM. I showed that aged Foxn1Tg mice have a higher number of TEC, and ETP; consequently, leading to attenuation of the age-associated decline in thymopoiesis. In addition, the decline in the number of bone marrow-derived T cell progenitors is prevented in Foxn1Tg. Using adaptive transfer experiments, I demonstrated that the aged Foxn1Tg BM microenvironment promotes the development of T cell progenitors. Lastly, I have identified a novel population of cells in the BM that express Foxn1. Taken together this data suggests that the presence of Foxn1 expressing cells in the thymus and BM contribute to niches that play an important role in the maintenance of T cell progenitors with age.

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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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