DATE: Wednesday, January 11th, 2017
SPEAKERS: Sally Kent, PhD
University of Massachusetts Medical School
Maki Nakayama, MD, PhD
University of Colorado
Click here to view a recording of the webinar.
Broad Repertoire of Autoreactive T Cells from the Islets of Donors with Type 1 Diabetes:
In this webinar, we will be discussing our recent study on the analyses of live, autoreactive CD4 and CD8 T cells derived directly from the islets of donors with type 1 diabetes (Babon et. al., Nature Medicine, 2016, PMID: 27798614). We will be discussing the islet samples, handling of the islets, isolation and growth of T cells from the islets, and analyses of their autoreactivity and function to known islet peptide targets and to modified peptides. We will also discuss current and future studies in these ongoing analyses.
Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes:
Type 1 diabetes results from chronic autoimmune destruction of insulin-producing beta cells within pancreatic islets. While insulin is a critical self-antigen in animal models of autoimmune diabetes, due to extremely limited access to pancreas samples, little is known about human antigenic targets for islet-infiltrating T-cells. In this webinar, we will show that proinsulin peptides are targeted by islet-infiltrating T-cells from type 1 diabetes patients. We identified hundreds of T-cells from inflamed pancreatic islets of three young type 1 diabetes organ donors with a short disease duration with high risk HLA genes using a direct T-cell receptor (TCR) sequencing approach without long-term cell culture. Among 85 selected CD4 TCRs tested for reactivity to preproinsulin peptides presented by diabetes-susceptible HLA-DQ and -DR molecules, one T-cell recognized C-peptide amino acids 19-35, and two clones from separate donors responded to insulin B chain amino acids 9-23 (B:9-23) which is known to be a critical self-antigen driving disease progress in animal models of autoimmune diabetes. These B:9-23-specific T-cells from islets responded to whole proinsulin and islets, while previously identified B:9-23 responsive clones from peripheral blood did not, highlighting the importance of proinsulin-specific T-cells in the islet microenvironment.