UMMS Affiliation

Diabetes Center of Excellence, Department of Medicine, Division of Diabetes

Publication Date


Document Type



Endocrine System Diseases | Endocrinology | Endocrinology, Diabetes, and Metabolism | Immune System Diseases | Nutritional and Metabolic Diseases


Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.


T cell receptors, antigens, epitopes, islets, preproinsulin, type 1 diabetes

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Copyright © 2021 Landry, Anderson, Russ, Yu, Kent, Atkinson, Mathews, Michels and Nakayama. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

DOI of Published Version



Landry LG, Anderson AM, Russ HA, Yu L, Kent SC, Atkinson MA, Mathews CE, Michels AW, Nakayama M. Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors. Front Endocrinol (Lausanne). 2021 Mar 25;12:622647. doi: 10.3389/fendo.2021.622647. PMID: 33841327; PMCID: PMC8027116. Link to article on publisher's site

Journal/Book/Conference Title

Frontiers in endocrinology

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.