Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
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
_version_ 1783621997355335680
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
work_keys_str_mv AT kimheejoo targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT perovanovicjelena targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT shakyaarvind targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT shenzuolian targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT germancodyn targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT ibarraandrea targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT jafekjillianl targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT linnaipin targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT evavoldbriand targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT choudannyhc targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT jensenpetere targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT hexiao targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes
AT tantindean targetingtranscriptionalcoregulatorocabpou2af1blocksactivatedautoreactivetcellsinthepancreasandtype1diabetes