BME PhD Dissertation Defense: Zhuoying (Joey) Huang

Title: "Synthetic Receptor Engineering for Immune Control: Precision Targeting of Autoreactive T Cells and Quantitative Dissection of T Cell Fate"

Advisory Committee: Wilson Wong, PhD – BME (Research Advisor) Ahmad (Mo) Khalil, PhD – BME (Chair) Jennifer Snyder-Cappione, PhD – Virology, Immunology, Microbiology Brian Cleary, PhD – CDS, BME, Biology Aurelie Edwards, PhD – BME

Abstract: Immune cell engineering offers a powerful framework for both developing precision immunotherapies and probing the mechanisms that govern T cell differentiation. My doctoral research leveraged synthetic receptor platforms as modular systems to reprogram immune specificity while quantitatively interrogating how signaling and environmental inputs shape T cell fate decisions. This work pursued two complementary directions: engineering therapeutic immune targeting strategies and using synthetic receptors as tools to dissect T cell state transitions. In the first direction, I developed precision immunotherapy strategies for autoimmune disease. Using peptide–major histocompatibility complex (pMHC)-based antigen recognition domains, I engineered T cell receptor–targeting modalities to selectively eliminate autoreactive T cells implicated in Type 1 diabetes. These targeting modules were incorporated into conventional chimeric antigen receptors (CARs) and mRNA-delivered bispecific T cell engagers. Through these studies, I established modular approaches for antigen-directed immune modulation and evaluated their functionality using in vitro T cell systems. In the second direction, I repurposed engineered split universal programmable (SUPRA) CAR systems as synthetic biology tools to investigate T cell signaling and differentiation. By independently tuning CD3ζ and costimulatory signaling inputs, I decoupled receptor identity from signaling strength and duration, enabling systematic mapping of how chronic stimulation shapes activation, differentiation, and exhaustion. Longitudinal high-dimensional phenotyping and composite functional indices revealed that T cell exhaustion emerges as a progressive, multidimensional state governed by integrated signaling strength and prior stimulation history. Together, this work demonstrates how synthetic receptor systems can serve as both therapeutic platforms and quantitative probes of immune regulation, providing design principles for next-generation immunotherapies and advancing systems-level understanding of T cell fate.