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Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes
The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell–specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We develope...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731945/ https://www.ncbi.nlm.nih.gov/pubmed/33295943 http://dx.doi.org/10.1084/jem.20200533 |
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author | Kim, Heejoo Perovanovic, Jelena Shakya, Arvind Shen, Zuolian German, Cody N. Ibarra, Andrea Jafek, Jillian L. Lin, Nai-Pin Evavold, Brian D. Chou, Danny H.-C. Jensen, Peter E. He, Xiao Tantin, Dean |
author_facet | Kim, Heejoo Perovanovic, Jelena Shakya, Arvind Shen, Zuolian German, Cody N. Ibarra, Andrea Jafek, Jillian L. Lin, Nai-Pin Evavold, Brian D. Chou, Danny H.-C. Jensen, Peter E. He, Xiao Tantin, Dean |
author_sort | Kim, Heejoo |
collection | PubMed |
description | The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell–specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell–specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8(+) T cell receptor specificities associated with diabetes pathogenesis. CD4(+) clones associated with diabetes were present but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice but diminished in monoclonal models specific to artificial or neoantigens. Rationally designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels and reduced T cell infiltration and proinflammatory cytokine expression in newly diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition. |
format | Online Article Text |
id | pubmed-7731945 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-77319452021-09-01 Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes Kim, Heejoo Perovanovic, Jelena Shakya, Arvind Shen, Zuolian German, Cody N. Ibarra, Andrea Jafek, Jillian L. Lin, Nai-Pin Evavold, Brian D. Chou, Danny H.-C. Jensen, Peter E. He, Xiao Tantin, Dean J Exp Med Article The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell–specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell–specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8(+) T cell receptor specificities associated with diabetes pathogenesis. CD4(+) clones associated with diabetes were present but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice but diminished in monoclonal models specific to artificial or neoantigens. Rationally designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels and reduced T cell infiltration and proinflammatory cytokine expression in newly diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition. Rockefeller University Press 2020-12-09 /pmc/articles/PMC7731945/ /pubmed/33295943 http://dx.doi.org/10.1084/jem.20200533 Text en © 2020 Kim et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Kim, Heejoo Perovanovic, Jelena Shakya, Arvind Shen, Zuolian German, Cody N. Ibarra, Andrea Jafek, Jillian L. Lin, Nai-Pin Evavold, Brian D. Chou, Danny H.-C. Jensen, Peter E. He, Xiao Tantin, Dean Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes |
title | Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes |
title_full | Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes |
title_fullStr | Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes |
title_full_unstemmed | Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes |
title_short | Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes |
title_sort | targeting transcriptional coregulator oca-b/pou2af1 blocks activated autoreactive t cells in the pancreas and type 1 diabetes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731945/ https://www.ncbi.nlm.nih.gov/pubmed/33295943 http://dx.doi.org/10.1084/jem.20200533 |
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