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Type of Resource (primo): dissertations
Name: Personal
Name: Personal
Name: Personal
Name: Personal
Name: Personal
Name: Corporate
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Note: thesis: Thesis (Ph. D.)--Brown University, 2024
Genre (aat): theses
Abstract: Estrogen, the major female sex hormone has been linked with immune response disparity between males and females. However, the exact mechanism by which estrogen impacts our ability to fight viral infection and development of immunologic memory remains unknown. CD8 T cells represent the primary protective mechanism against viruses and cancer. Here we aim to understand how CD8 T cell mediated antiviral immune response is regulated by estrogen. Systemic LCMV infection in ovariectomized female mice generated lower virus-specific memory CD8 T cells compared to sham surgery controls. To check if this reduction in memory response is CD8 T cell intrinsic, I generated a transgenic virus specific estrogen receptor-alpha deficient CD8 mouse line (ESR1 KO). Using a co-adoptive transfer model, I compared the differentiation of ESR1 KO and control CD8 T cells in both systemic LCMV and local influenza infection. The lack of estrogen signaling resulted in reduced abundance of effector CD8 T cells in the context of both infections. ESR1 KO CD8 T cells also displayed reduced cytotoxic ability. In vitro studies revealed that the CD8 T cell expansion was primarily impacted by the lack of estrogen signaling, whereas activation and cellular apoptosis remain unchanged. Altogether, this suggests a crucial role of sex steroid estrogen in initial effector CD8 T cell differentiation, that has significant ramification for generation of protective immune responses in pathological or physiological estrogen deficiency. In addition, CD8 T cells in the female reproductive tract are a crucial component of the local antiviral defense. Within the vaginal mucosa, CD8 T cells reside in close contact with vaginal epithelial cells and the CD8-epithelium crosstalk is thought be important for maintenance and function of CD8 T cells. Estrogen has been shown to influence the epithelial cell proliferation and integrity. However, if this estrogen mediated modulation of epithelial biology could also affect resident CD8 T cells in the vaginal mucosa has not been investigated. This study aims to elucidate how the vaginal epithelium modulates CD8 T cell differentiation in the presence or absence of estrogen, utilizing an in vitro organoid model of mouse vaginal epithelium. To identify the mechanism, biochemical or structural changes of vaginal epithelium by estrogen, I used vaginal epithelium organoid model and co cultured them with CD8 T cells. I found that estrogen treatment promoted the growth and formation of vaginal epithelial organoids, while pharmacological inhibition of estrogen in the same organoid system significantly reduced the overall size and number of these organoids. Overall, our study shows that estrogen plays a significant role in vaginal epithelium proliferation and intact estrogen signaling might be important in differentiation of resident memory CD8 T cells in the vaginal mucosa.
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Subject (fast) (authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/00915634")
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