Abstract IA04: Investigating T cell immunobiology using genetically engineered models

Abstract T cells are found in various contexts, from infections to cancers, in healthy and diseased tissues. While their functions vary across these distinct contexts, the underlying mechanisms governing their function in specific situations remain less well understood. To address this gap, my lab develops genetically engineered animal models that enable us to study antigen-specific CD8 and CD4 T cell responses to infections, cancers, and healthy tissues. These models replicate tissue biology that is challenging to study in other settings, such as the presence of tumor-associated tertiary lymphoid structures. This allows us to investigate the natural and therapeutic functions of T cells in various human-relevant microenvironments. Our models provide maximum flexibility for comparing conditions, identifying differences, and testing mechanisms. We adopt a developmental biology lens to study T cell responses, assessing their differentiation trajectories from naive to stem-like to terminal cells. Additionally, we utilize advanced technologies like high-dimensional flow cytometry, single-cell transcriptomics, TCR sequencing, and CRISPR-based knockout techniques (including perturbSEQ) to investigate natural differentiation trajectories over time and across tissues. Current studies focus on utilizing our models and techniques to address questions pertinent to the anti-tumor immune response, chronic and acute infections, and mechanisms that prevent T cells from causing immunopathology in healthy tissues (immunologic tolerance). Citation Format: Nikhil Joshi. Investigating T cell immunobiology using genetically engineered models [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr IA04.