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

Author:

Liu Baoyu1,Hood Jennifer D.2,Kolawole Elizabeth M.1,Woodruff Derek M.3,Vignali Dario A.4,Bettini Maria5ORCID,Evavold Brian D.1ORCID

Affiliation:

1. Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT

2. Department of Microbiology and Immunology, Emory University, Atlanta, GA

3. University of Utah School of Medicine, Salt Lake City, UT

4. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA

5. Department of Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Houston, TX

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.

Funder

American Diabetes Association

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Reference48 articles.

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