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T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response

BACKGROUND: Treatments for autoimmune diseases aim to dampen autoreactivity while preserving normal immune function. In CD4(+) T cells, the transcription factor Oct1/Pou2f1 is a dispensable transcription factor for T cell development and response to primary infection, but promotes expression of targ...

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Autores principales: Kim, Heejoo, Dickey, Laura, Stone, Colleen, Jafek, Jillian L., Lane, Thomas E., Tantin, Dean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607600/
https://www.ncbi.nlm.nih.gov/pubmed/31266507
http://dx.doi.org/10.1186/s12974-019-1523-3
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author Kim, Heejoo
Dickey, Laura
Stone, Colleen
Jafek, Jillian L.
Lane, Thomas E.
Tantin, Dean
author_facet Kim, Heejoo
Dickey, Laura
Stone, Colleen
Jafek, Jillian L.
Lane, Thomas E.
Tantin, Dean
author_sort Kim, Heejoo
collection PubMed
description BACKGROUND: Treatments for autoimmune diseases aim to dampen autoreactivity while preserving normal immune function. In CD4(+) T cells, the transcription factor Oct1/Pou2f1 is a dispensable transcription factor for T cell development and response to primary infection, but promotes expression of target genes, including Il2 and Ifng, under conditions of antigen reencounter. As a result, they are more strongly expressed upon secondary stimulation. Such repeated antigen encounters occur in memory recall responses, in autoimmunity where self-antigen can be recognized multiple times, and in chronic infection where foreign antigen is persistent. Based on these previous findings, we hypothesized that Oct1 loss would protect animals from autoimmunity but maintain normal responses to pathogens in the CNS. OBJECTIVE: We used a conditional mouse Oct1 (Pou2f1) allele and a CD4-Cre driver to determine the effect of T cell-specific Oct1 loss on autoimmune- and viral-induced neuroinflammation using an autoantigen-driven EAE model of autoimmunity and a JHMV model of viral infection. RESULTS: Oct1 conditional deletion mitigated clinical scores and reduced infiltrating T cells and cytokine production in the EAE model. Consistently, Oct1-deficient CD4(+) T cells stimulated in vitro showed increased expression of markers associated with T cell anergy, particularly in the absence of co-stimulatory signals. In contrast, anti-viral T cell effector functions are intact in the absence of Oct1, with no changes in neuroinflammation, infiltrating T cells or cytokine production. CONCLUSION: Our findings uncover a significant difference between the effect of Oct1 loss on autoimmune and anti-pathogen responses, which potentially could be exploited for therapeutic benefit. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-019-1523-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-66076002019-07-12 T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response Kim, Heejoo Dickey, Laura Stone, Colleen Jafek, Jillian L. Lane, Thomas E. Tantin, Dean J Neuroinflammation Research BACKGROUND: Treatments for autoimmune diseases aim to dampen autoreactivity while preserving normal immune function. In CD4(+) T cells, the transcription factor Oct1/Pou2f1 is a dispensable transcription factor for T cell development and response to primary infection, but promotes expression of target genes, including Il2 and Ifng, under conditions of antigen reencounter. As a result, they are more strongly expressed upon secondary stimulation. Such repeated antigen encounters occur in memory recall responses, in autoimmunity where self-antigen can be recognized multiple times, and in chronic infection where foreign antigen is persistent. Based on these previous findings, we hypothesized that Oct1 loss would protect animals from autoimmunity but maintain normal responses to pathogens in the CNS. OBJECTIVE: We used a conditional mouse Oct1 (Pou2f1) allele and a CD4-Cre driver to determine the effect of T cell-specific Oct1 loss on autoimmune- and viral-induced neuroinflammation using an autoantigen-driven EAE model of autoimmunity and a JHMV model of viral infection. RESULTS: Oct1 conditional deletion mitigated clinical scores and reduced infiltrating T cells and cytokine production in the EAE model. Consistently, Oct1-deficient CD4(+) T cells stimulated in vitro showed increased expression of markers associated with T cell anergy, particularly in the absence of co-stimulatory signals. In contrast, anti-viral T cell effector functions are intact in the absence of Oct1, with no changes in neuroinflammation, infiltrating T cells or cytokine production. CONCLUSION: Our findings uncover a significant difference between the effect of Oct1 loss on autoimmune and anti-pathogen responses, which potentially could be exploited for therapeutic benefit. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-019-1523-3) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-03 /pmc/articles/PMC6607600/ /pubmed/31266507 http://dx.doi.org/10.1186/s12974-019-1523-3 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Kim, Heejoo
Dickey, Laura
Stone, Colleen
Jafek, Jillian L.
Lane, Thomas E.
Tantin, Dean
T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response
title T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response
title_full T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response
title_fullStr T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response
title_full_unstemmed T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response
title_short T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response
title_sort t cell-selective deletion of oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607600/
https://www.ncbi.nlm.nih.gov/pubmed/31266507
http://dx.doi.org/10.1186/s12974-019-1523-3
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