UMMS Affiliation

Department of Medicine, Division of Endocrinology and Metabolism

Publication Date

2021-06-01

Document Type

Article

Disciplines

Endocrine System Diseases | Endocrinology, Diabetes, and Metabolism | Genetics and Genomics | Immune System Diseases | Immunity | Immunopathology | Nutritional and Metabolic Diseases

Abstract

Genetic analyses of human type 1 diabetes (T1D) have yet to reveal a complete pathophysiologic mechanism. Inbred rats with a high-risk class II major histocompatibility complex (MHC) haplotype (RT1B/D(u)) can illuminate such mechanisms. Using T1D-susceptible LEW.1WR1 rats that express RT1B/D(u) and a susceptible allele of the Ubd promoter, we demonstrate that germline knockout of Tcrb-V13S1A1, which encodes the Vbeta13a T cell receptor beta chain, completely prevents diabetes. Using the RT1B/D(u)-identical LEW.1W rat, which does not develop T1D despite also having the same Tcrb-V13S1A1 beta chain gene but a different allele at the Ubd locus, we show that knockout of the Ubash3a regulatory gene renders these resistant rats relatively susceptible to diabetes. In silico structural modeling of the susceptible allele of the Vbeta13a TCR and its class II RT1(u) ligand suggests a mechanism by which a germline TCR beta chain gene could promote susceptibility to T1D in the absence of downstream immunoregulation like that provided by UBASH3A. Together these data demonstrate the critical contribution of the Vbeta13a TCR to the autoimmune synapse in T1D and the regulation of the response by UBASH3A. These experiments dissect the mechanisms by which MHC class II heterodimers, TCR and regulatory element interact to induce autoimmunity.

Keywords

MHC, TCR, autoimmunity, genetics, immunogenetics, rat, type 1 diabetes

Rights and Permissions

Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

DOI of Published Version

10.3390/genes12060852

Source

Mordes JP, Cort L, Liu Z, Eberwine R, Blankenhorn EP, Pierce BG. T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes. Genes (Basel). 2021 Jun 1;12(6):852. doi: 10.3390/genes12060852. PMID: 34205929; PMCID: PMC8227067. Link to article on publisher's site

Journal/Book/Conference Title

Genes

Related Resources

Link to Article in PubMed

PubMed ID

34205929

Creative Commons License

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

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