Development of novel model to measure TCR signal strength in dual TCR cells

/Abstract Our laboratory studies the subset (~16%) of T lymphocytes that naturally co-express 2 T cell antigen receptor (TCR) clonotypes, which have been demonstrated to have selectively increased reactivity against certain types of antigenic ligands. Despite the obvious implications for increased breadth of antigenic recognition by these cells, dual TCR T cells have been largely unstudied, owing to limited availability of tools for effectively studying them. Our group has developed several unique tools for studying dual TCR cells, and have provided evidence demonstrating that dual TCR expression is important in T cell development and that dual TCR cells have selective ability to recognize some types of ligands. Based on published and preliminary studies demonstrating functional effect of dual TCR cell co-expression in directing T cell differentiation and responses, we hypothesize that dual TCR co-expression may potentiate TCR signaling, possibly through cooperative effects. This could have significant impact on TCR-mediated signals instructing T cell differentiation and functional responses. Our development of the B6.TCRA-GFP/RFP dual TCR reporter mouse has been a unique and invaluable tool to identify unappreciated effects of dual TCR co-expression. This project proposes to generate and validating a novel transgenic mouse model combining a new B6.TCRA-AmCy reporter mouse with the well-established Nur77-GFP reporter model to enable assessment of TCR signal strength in single- and dual TCR cells. We propose that generating and validating these reagents will open significant new areas of investigation to understand fundamental T cell biology and the specific roles of dual TCR cells in protective and pathologic T cell function. Project Number: 1R03AI189581-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Gerald Morris | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $159,500 | Activity Code: R03 | Study Section: Molecular and Structural Immunology Study Section[MSI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R03AI18958101A1