Tu140 - Impaired Thymocyte Selection in Type 1 Diabetic Immune Systems

Rachel Madley – Medicine, Columbia Center for Translational Immunology – Columbia University Irving Medical Center; Nichole Danzl – Medicine, Columbia Center for Translational Immunology – Columbia University Irving Medical Center; Grace Nauman – Medicine, Columbia Center for Translational Immunology – Columbia University Irving Medical Center; Mohsen Khosravi Maharlooei – Medicine, Columbia Center for Translational Immunology – Columbia University Irving Medical Center; Katherine Long – Medicine, Columbia Center for Translational Immunology – Columbia University Irving Medical Center; Remi Creusot – Medicine, Columbia Center for Translational Immunology – Columbia University Irving Medical Center; Maki Nakayama – Barbara Davis Center for Childhood Diabetes – University of Colorado School of Medicine; Bart Roep – Internal Medicine – Leiden University Medical Center; Robert Winchester – Medicine, Columbia Center for Translational Immunology – Columbia University Irving Medical Center; Megan Sykes – Medicine, Columbia Center for Translational Immunology – Columbia University Irving Medical Center

Abstract Text: The extent to which failure of thymic selection contributes to human Type 1 diabetes (T1D) is unknown. To address potential hematopoietic stem cell (HSC)-intrinsic abnormalities, we compared thymic selection in human immune system (HIS) mice generated from healthy control (HC) and T1D patient HSCs. Negative selection of an islet autoreactive TCR was diminished in T1D-derived compared to HC immune systems. Differentiation of thymocytes with this TCR to the T-regulatory (Treg) cell lineage occurred in HC thymocytes but was impaired in T1D systems. T1D-associated single nucleotide polymorphisms (SNPs) in SH2B3 and Erk/MAP kinase pathway-associated genes were associated with impaired thymocyte negative selection. Single cell gene expression analysis revealed that a major population of thymocytes apparently undergoing negative selection, with high expression of genes in the TCR signaling pathway and in pro-apoptotic pathways, was absent among T1D thymocytes. Additionally, T1D thymocytes demonstrated differential expression of multiple genes involved in thymic selection, including decreased expression of TCR signaling molecule Zap-70 and increased expression of anti-apoptotic genes compared to HC thymocytes. These studies provide the first direct evidence for impaired thymic negative selection and autoreactive Treg differentiation in T1D immune systems, and suggest genetic mechanisms through which selection is impaired, providing novel insights into T1D pathogenesis.