Investigating Mechanisms of T Cell Activation Through Lipid Modulation and Pediatric Immune Dysregulation Disorders
Abstract
T lymphocytes play a pivotal role in immune responses, transitioning from a predominantly naïve state in early childhood to memory and regulatory functions in adulthood. This work investigates the dynamic role of T cells in the adaptive immune system throughout various activation states. It explores the impact of unique mutations in key signaling proteins, ZAP-70 and STXBP2, on immune function. This research aims to unravel intricate changes in T cell functionality and molecular mechanisms contributing to immune dysregulation disorders.This thesis begins with an in-depth analysis of ZAP-70 combined immunodeficiency (CID), a severe autosomal recessive disorder characterized by abnormal T cell receptor signaling. We presented the novel case of an infant with a unique compound heterozygous mutation in ZAP-70. Molecular signaling alterations induced by these mutations were further elucidated through imaging and biochemical studies in transfected Jurkat cells, linking the mutations to observed immunological outcomes.Subsequently, this thesis focused on the regulatory mechanisms of DAG-mediated signaling for T cell functions, focusing on Extended-Synaptotagmins (E-Syts). This study identified E-Syts as key players in modulating DAG levels at the plasma membrane and endoplasmic reticulum junction sites, impacting T cell receptor signaling, cytotoxicity, degranulation, and cytokine production. Through the use of biochemical, immunological and advanced imaging techniques this work unveils a previously underappreciated role of E-Syts in regulating DAG dynamics in T cell signaling.This thesis further explores neonatal hemophagocytic lymphohistiocytosis (HLH) through a case of a newborn male with a maternally inherited heterozygous mutation in Syntaxin-Binding Protein-2 (STXBP2). Functional assays and biochemical studies were conducted revealing that the identified mutation acts in a dominant-negative manner, thus inhibiting degranulation and reducing cytolytic activity of CD8+ T cells while maintaining cellular localization of the protein.Overall, this body of work provides a comprehensive insight into the multidimensional roles of T cells in immune regulation and the intricate molecular mechanisms underlying immunodeficiencies and steady-state lipid modulating mechanisms, contributing to our understanding of the adaptive immune system and potential therapeutic interventions.
Subject Area
Immunology|Cellular biology|Biochemistry
Recommended Citation
Benavides, Nathalia, "Investigating Mechanisms of T Cell Activation Through Lipid Modulation and Pediatric Immune Dysregulation Disorders" (2024). ProQuest ETD Collection - Thomas Jefferson University. AAI30992698.
https://jdc.jefferson.edu/dissertations/AAI30992698
