108-OR: Islet-Derived Preproinsulin T Cell Receptor Sequences Are Present throughout the Stages of Type 1 Diabetes Development

Abstract

Type 1 diabetes (T1D) results from the T cell-mediated destruction of insulin-producing pancreatic β-cells as evidenced by CD8 and CD4 T cells being present within the inflamed islets of recent-onset T1D organ donors. We isolated, sequenced the T cell receptor (TCR) from ∼3,500 T cells in the residual islets of T1D organ donors (n=9), and determined antigen specificity to 41 preproinsulin-reactive T cells from these islet sequences. Among the T1D organ donor islet sequences, 32% are shared (identical Vβ, Jβ, CDR3β) within the peripheral blood of new-onset T1D patients that had sequencing done from whole blood DNA (n=162, 34x106 TCR sequences, Adaptive Biotechnologies). Similar numbers of sequences are shared between both CD4 and CD8 T cells. Furthermore, 53 unique sequences were disease-specific, as they were identified in <1% of TCR sequences from controls (n=786, 275x106 sequences), whereas they were detected in 54% of new-onset T1D patients (p<0.001). These disease-specific and preproinsulin-reactive TCR sequences are good candidates for biomarkers in T1D. Therefore, we next sequenced the TCR beta chains throughout the disease course of five participants in the Diabetes AutoImmunity Study in the Young (DAISY) at 4 time points (early in life, prior to islet autoantibody seroconversion, post-autoantibody seroconversion, and at T1D onset). 10% of these insulin-reactive TCR sequences, including those to hybrid insulin peptides, are present throughout the disease course. Interestingly, insulin-reactive CD4 TCRs were predominant early in life, while higher frequencies of both insulin-reactive CD8 and CD4 were present at clinical T1D diagnosis. With continued TCR sequencing from longitudinal patient samples across the stages of T1D and identifying antigen specificity to more islet-derived T cells outside of preproinsulin, TCR sequences from genomic DNA have the potential to be a powerful disease biomarker during the progression to clinical type 1 diabetes. Disclosure E. E. Baschal: None. A. W. Michels: Stock/Shareholder; Self; IM Therapeutics. A. M. Mitchell: None. K. Mcdaniel: None. A. Alkanani: None. T. Armstrong: None. L. Landry: None. K. Waugh: None. M. Rewers: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; RTI, Research Support; Self; Janssen Research & Development, LLC, JDRF. M. Nakayama: None. Funding National Institutes of Health (DK108868, DK110845, DK032083, DK099317, DK032493)