Checks and Balances of T cells in Inflammatory Environments

Abstract

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