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Author Notes:

Brian D. Evavold, Email: brian.evavold@path.utah.edu

B.L., J.D.H., and B.D.E. designed the experiments. B.L., J.D.H., and E.M.K. obtained 2D affinity data. B.L., J.D.H., and D.M.W. obtained T-cell functional data. B.L., J.D.H., and B.D.E. designed the experiments. B.L., J.D.H., and B.D.E. wrote the manuscript. D.A.V. and M.B. contributed to writing the manuscript. B.D.E. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors thank Laurel Ann Lawrence (Emory University) and Linda Morrison (University of Utah) for managing the mouse colony and screening of mice, Dr. Rustom Antia and Dr. Veronika Zarnitsyna (Emory University) for their expertise and guidance in statistical analysis, Dr. Cheng Zhu and his laboratory (Georgia Institute of Technology), Dr. Joseph Sabatino (Emory University) for technical support and advice with the micropipette adhesion frequency assay, and Hiran Thyagarajan, Mike Faust, Gavile Cathy, and Douglas Cornwall (University of Utah) for careful reading of the manuscript. The authors also thank the National Institutes of Health Tetramer Core Facility (Emory University) for providing all of the pMHC monomers and tetramers used in this study.

No potential conflicts of interest relevant to this article were reported.

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Research Funding:

Training support from National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (F31-DK-089932) was provided for J.D.H. This work was supported by NIH National Institute of Diabetes and Digestive and Kidney Diseases grant DK-089125 (D.A.V. and M.B.), National Institute of Allergy and Infectious Diseases grant AI-125301 (M.B.), National Institute of Neurological Disorders and Stroke grant NS-071518 (B.D.E.), and American Diabetes Association grant 1-09-IN-16 (B.D.E.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Endocrinology & Metabolism
  • TCR
  • KINETICS
  • SELF
  • AVIDITY
  • ONSET

A Hybrid Insulin Epitope Maintains High 2D Affinity for Diabetogenic T Cells in the Periphery

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Journal Title:

DIABETES

Volume:

Volume 69, Number 3

Publisher:

, Pages 381-391

Type of Work:

Article | Final Publisher PDF

Abstract:

β-Cell antigen recognition by autoreactive T cells is essential in type 1 diabetes (T1D) pathogenesis. Recently, insulin hybrid peptides (HIPs) were identified as strong agonists for CD4 diabetogenic T cells. Here, using BDC2.5 transgenic and NOD mice, we investigated T-cell recognition of the HIP2.5 epitope, which is a fusion of insulin C-peptide and chromogranin A (ChgA) fragments, and compared it with the WE14 and ChgA29–42 epitopes. We measured in situ two-dimensional affinity on individual live T cells from thymus, spleen, pancreatic lymph nodes, and islets before and after diabetes. Although preselection BDC2.5 thymocytes possess higher affinity than splenic BDC2.5 T cells for all three epitopes, peripheral splenic T cells maintained high affinity only to the HIP2.5 epitope. In polyclonal NOD mice, a high frequency (∼40%) of HIP2.5-specific islet T cells were identified at both prediabetic and diabetic stages comprising two distinct high- and low-affinity populations that differed in affinity by 100-fold. This high frequency of high- and low-affinity HIP2.5 T cells in the islets potentially represents a major risk factor in diabetes pathogenesis.

Copyright information:

© 2019 by the American Diabetes Association.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
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