Lipidomic discovery of physiological CD1 antigens and blockers for human T cells

Modified Project Summary/Abstract Section T cells control immune response during vaccination, autoimmunity and infection based on their recognition of antigens. This R01 resubmission proposal studies lipid antigens for T cells by taking advantage of a sensitive lipidomics platform that can comprehensively detect lipids bound to CD1 antigen presenting molecules. By detecting hundreds of lipids bound to human CD1a, CD1b, CD1c and CD1d, we will determine the general patterns of lipid capture by cellular CD1 proteins. By separating CD1 proteins that do and do not bind to T cell receptors, lipidome-scale experiments will identify chemical patterns in natural lipids that lead to activation and blockade of T cell response. Based on a prior program that identified CD1a ligands that block T cell response in vivo, we will determine the structures of CD1b, CD1c and CD1d ligands that are inhibitors for T cells. Finally, optimized blockers will be tested ex vivo using polyclonal human T cells and CD1 tetramers, with an emphasis on CD1a and CD1c blockers. Overall, we seek to develop anti-inflammatory therapies that can act through specific blockade of human T cells. Unlike the MHC antigen presenting molecules, CD1 proteins are non-polymorphic, meaning that once the CD1-lipid binding patterns are described, they will apply to nearly all humans. Project Number: 1R01AI189471-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: DAVID MOODY | Institution: BRIGHAM AND WOMEN'S HOSPITAL, BOSTON, MA | Award Amount: $893,459 | Activity Code: R01 | Study Section: Molecular and Structural Immunology Study Section[MSI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18947101A1