DOI
https://doi.org/10.25772/18MQ-P731
Defense Date
2005
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Microbiology & Immunology
First Advisor
Dr. Mitzi Nagarkatti
Abstract
Estrogens have the ability to alter the immune system. Diethylstilbestrol (DES), asynthetic estrogen, is known to have estrogenic activity and induce thymic alterations.We investigated the mechanism by which DES is able to alter T cells and thus theimmune system. First, we studied the effect of DES on mature T cells by using the T cellleukemia cell line, Jurkat. We found that DES treatment reduced cell viability andincreased apoptosis. Additionally, apoptosis was found to involve both death receptorand mitochondria1 pathways. Furthermore, estrogen receptor beta was found to beexpressed in these cells and increased following DES treatment. Secondly, we studiedthe effect of DES on developing T cells using two different mouse models, timed pregnant and HY-TCR transgenic. The pregnant mouse model showed that DESexposure in utero reduced thymic cell viability and induced apoptosis at gestational day(gd)-17. Apoptosis was found to involve the death receptor pathway. Additionally,alterations in T cell subsets was most pronounced at gd-17 as well. The HY-TCR tgmouse model showed that DES exposure altered both positive and negative selection of Tcells. Furthermore, DES was found to alter the ability of T cells to proliferate during animmune response. Finally, we studied the intrathymic interaction between thymicstromal cells and thymic T cells. We found that cel1:cell interaction was important forinducing T cell apoptosis in the thymus. Additionally, FasL expression was increased onthymic stromal cells following DES exposure. Furthermore, the presence of both FasL onstromal cells and Fas on T cells was important for inducing T cell apoptosis in thethymus.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
June 2008