Regulatory T cells (Tregs) are endowed with the ability to recognize a wide array of tissues. This recognition is conferred by the diversity of T Cell Receptors (TCRs) expressed on the surface of these cells. Prior studies in animal models suggest that treating mice with Tregs specific to pancreatic beta cell proteins is a potent means for protecting beta cells from the destructive properties of effector T cells responsible for disease development. Our laboratory is developing protocols to change the specificity of Tregs by way of gene transfer of a new TCR specific for islets. The ultimate goals of this approach are to shut down the autoimmune response directed at pancreatic beta cells, while simultaneously leaving the protective immune response to bacteria and viruses intact.
Project Title: Engineered Tregs to block autoantibody development and progression of type 1 diabetes. Project Period: 09/01/2019 – 08/31/2020
Project aims are to generate human and murine Tfr avatars specific for pancreatic b-cell antigens, to perform In vitro testing of human and murine Tfr avatars for long-term stability and function, and to develop human and murine CXCR5+ Tfr avatars expressing TCRs specific for islet autoantigens as a potential cellular therapy targeting the Tfh:B cell interactions that are required to facilitate islet antigen reactive B cell maturation and Ig class switching in the pLN.
Project Title: Single cell sequencing for islet-reactive T cell clonotype and transcript signatures. Project Period: 06/01/2019 – 05/31/2022
Project aims are to determine if islet-autoreactive CD8 TCR clonotypes are expanded in peripheral blood and whether these cells have a unique transcript signature, to determine TCR clonotype sharing of islet-reactive T cells across tissues in stage 4 T1D donors, and whether transcriptome is impacted by tissue type or by islet vs non-self reactivities, and to identify islet-reactive CD8 TCR clonotypes in bulk-sequenced peripheral TCR repertoires to determine if shared TCR signature(s) present in the periphery of stage 4 T1D reflect the autoreactive repertoire.