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T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes
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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227067/ https://www.ncbi.nlm.nih.gov/pubmed/34205929 http://dx.doi.org/10.3390/genes12060852 |
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author | Mordes, John P. Cort, Laura Liu, Zhijun Eberwine, Ryan Blankenhorn, Elizabeth P. Pierce, Brian G. |
author_facet | Mordes, John P. Cort, Laura Liu, Zhijun Eberwine, Ryan Blankenhorn, Elizabeth P. Pierce, Brian G. |
author_sort | Mordes, John P. |
collection | PubMed |
description | 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 Vβ13a T cell receptor β 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 β 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 Vβ13a TCR and its class II RT1(u) ligand suggests a mechanism by which a germline TCR β 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 Vβ13a 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. |
format | Online Article Text |
id | pubmed-8227067 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-82270672021-06-26 T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes Mordes, John P. Cort, Laura Liu, Zhijun Eberwine, Ryan Blankenhorn, Elizabeth P. Pierce, Brian G. Genes (Basel) Article 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 Vβ13a T cell receptor β 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 β 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 Vβ13a TCR and its class II RT1(u) ligand suggests a mechanism by which a germline TCR β 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 Vβ13a 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. MDPI 2021-06-01 /pmc/articles/PMC8227067/ /pubmed/34205929 http://dx.doi.org/10.3390/genes12060852 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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/). |
spellingShingle | Article Mordes, John P. Cort, Laura Liu, Zhijun Eberwine, Ryan Blankenhorn, Elizabeth P. Pierce, Brian G. T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes |
title | T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes |
title_full | T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes |
title_fullStr | T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes |
title_full_unstemmed | T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes |
title_short | T Cell Receptor Genotype and Ubash3a Determine Susceptibility to Rat Autoimmune Diabetes |
title_sort | t cell receptor genotype and ubash3a determine susceptibility to rat autoimmune diabetes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227067/ https://www.ncbi.nlm.nih.gov/pubmed/34205929 http://dx.doi.org/10.3390/genes12060852 |
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