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Checks and Balances of T cells in Inflammatory Environments

Dadey, Rebekah (2021) Checks and Balances of T cells in Inflammatory Environments. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The immune system is composed of many checks and balances that are critical to limiting disease and maintaining homeostasis. T cells are critical regulators of this balance. For example, CD8+ T cells can limit diseases such as cancer and infection through induction of apoptosis in malignant and infected cells, respectively. Conversely, Regulatory T cells (Tregs), a subset of CD4+ T cells, are a suppressive population that can limit overt T cell activation and prevent autoimmunity.
However, these checks and balances can be potentially damaging if they are off-balance. CD8+ can inappropriately induce cell death of various cells which can induce disease. For example, cytotoxicity towards pancreatic beta cells, can induce autoimmune diabetes. Likewise, Tregs can detrimentally suppress T cell activation and function in the tumor microenvironment (TME) to limit clearance of the tumor. Therefore, identifying these mechanisms and regulation of these mechanisms of inappropriate function in inflammatory environments will be critical to limit disease.
Therefore, I examined how this balance may be maintained through epigenetic regulation in the TME and production of cytotoxic molecules in the TME and diabetic islet. Specifically, in Chapter 3, I demonstrate that Tregs alter their epigenome to aid in their suppression of the anti-tumor response. In Chapter 4, I show that Tregs do not require TNF-related apoptosis-inducing ligand (TRAIL) as a means of suppression in the TME nor diabetic islet but rather are capable of using other suppressive molecules in its absence. In Chapter 5, I demonstrate CD8+ T cell-restricted deletion of Tnfsf10 leads to almost complete protection from autoimmune diabetes. Understanding this regulation of checks and balances may aid in future therapeutic approaches to cancer and autoimmune disease.
In addition to my thesis study, Appendix A shows data in which I examined various models of tumor growth in a mouse model with genetic deletion of Neuropilin-1 (Nrp1) on Tregs and Appendix B shows data in which I examined the role of Nrp1 on Tregs in fetal maternal tolerance. Finally Appendix C identifies publications that I have contributed to and awards that I have received during my graduate training.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Dadey, Rebekahred61@pitt.edured61
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorVignali,
Committee ChairRay,
Committee MemberDelgoffe,
Committee MemberPoholek,
Committee MemberKostka,
Date: 2 August 2021
Date Type: Publication
Defense Date: 1 July 2021
Approval Date: 2 August 2021
Submission Date: 5 July 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 183
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Immunology, Cancer Immunology, Regulatory T cells, TRAIL, epigenetics
Related URLs:
Date Deposited: 02 Aug 2021 17:32
Last Modified: 02 Aug 2023 05:15


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