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OX40 signaling is involved in the autoactivation of CD4(+)CD28(−) T cells and contributes to the pathogenesis of autoimmune arthritis

BACKGROUND: CD4(+)CD28(−) T cells exhibit autoreactive potential in autoimmune disorders, including rheumatoid arthritis (RA). It is not well known which costimulator functions as an alternative second signal in the activation of this subset after CD28 expression is downregulated. Tumor necrosis fac...

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Autores principales: Jiang, Juean, Liu, Cuiping, Liu, Mi, Shen, Yu, Hu, Xiaohan, Wang, Qin, Wu, Jian, Wu, Min, Fang, Qi, Zhang, Xueguang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359925/
https://www.ncbi.nlm.nih.gov/pubmed/28320444
http://dx.doi.org/10.1186/s13075-017-1261-9
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author Jiang, Juean
Liu, Cuiping
Liu, Mi
Shen, Yu
Hu, Xiaohan
Wang, Qin
Wu, Jian
Wu, Min
Fang, Qi
Zhang, Xueguang
author_facet Jiang, Juean
Liu, Cuiping
Liu, Mi
Shen, Yu
Hu, Xiaohan
Wang, Qin
Wu, Jian
Wu, Min
Fang, Qi
Zhang, Xueguang
author_sort Jiang, Juean
collection PubMed
description BACKGROUND: CD4(+)CD28(−) T cells exhibit autoreactive potential in autoimmune disorders, including rheumatoid arthritis (RA). It is not well known which costimulator functions as an alternative second signal in the activation of this subset after CD28 expression is downregulated. Tumor necrosis factor receptor superfamily member OX40 is a key costimulator in the activation of T cells. The aim of this study was to investigate the costimulatory effects of OX40 on CD4(+)CD28(−) T cells in autoimmune arthritis. METHODS: Clinical samples were collected from patients with RA and control subjects. Collagen-induced arthritis (CIA) was induced with collagen type II (CII) in DBA/1 mice. The CD4(+)CD28(−)OX40(+) T-cell subset and its cytokine production were detected by flow cytometry. After T-cell purification, adoptive transfer was performed in CIA mice. The regulatory role of OX40 was determined by blocking experiments in vitro and in vivo. RESULTS: OX40 and OX40L were abnormally expressed in patients with RA and CIA mice. Further analysis showed that CD4(+)CD28(−)OX40(+) T cells accumulated in patients with RA and in animal models. These cells produced higher levels of proinflammatory cytokines and were closely correlated with the clinicopathological features of the affected individuals. Adoptive transfer of CII-specific CD4(+)CD28(−)OX40(+) T cells remarkably aggravated arthritic development and joint pathology in CIA mice. Moreover, OX40 blockade significantly reduced the proinflammatory responses and ameliorated arthritis development. CONCLUSIONS: OX40 acts as an alternative costimulator of CD4(+)CD28(−) T cells and plays a pathogenic role in autoimmune arthritic development, suggesting that it is a potential target for immunomodulatory therapy of RA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-017-1261-9) contains supplementary material, which is available to authorized users.
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spelling pubmed-53599252017-03-22 OX40 signaling is involved in the autoactivation of CD4(+)CD28(−) T cells and contributes to the pathogenesis of autoimmune arthritis Jiang, Juean Liu, Cuiping Liu, Mi Shen, Yu Hu, Xiaohan Wang, Qin Wu, Jian Wu, Min Fang, Qi Zhang, Xueguang Arthritis Res Ther Research Article BACKGROUND: CD4(+)CD28(−) T cells exhibit autoreactive potential in autoimmune disorders, including rheumatoid arthritis (RA). It is not well known which costimulator functions as an alternative second signal in the activation of this subset after CD28 expression is downregulated. Tumor necrosis factor receptor superfamily member OX40 is a key costimulator in the activation of T cells. The aim of this study was to investigate the costimulatory effects of OX40 on CD4(+)CD28(−) T cells in autoimmune arthritis. METHODS: Clinical samples were collected from patients with RA and control subjects. Collagen-induced arthritis (CIA) was induced with collagen type II (CII) in DBA/1 mice. The CD4(+)CD28(−)OX40(+) T-cell subset and its cytokine production were detected by flow cytometry. After T-cell purification, adoptive transfer was performed in CIA mice. The regulatory role of OX40 was determined by blocking experiments in vitro and in vivo. RESULTS: OX40 and OX40L were abnormally expressed in patients with RA and CIA mice. Further analysis showed that CD4(+)CD28(−)OX40(+) T cells accumulated in patients with RA and in animal models. These cells produced higher levels of proinflammatory cytokines and were closely correlated with the clinicopathological features of the affected individuals. Adoptive transfer of CII-specific CD4(+)CD28(−)OX40(+) T cells remarkably aggravated arthritic development and joint pathology in CIA mice. Moreover, OX40 blockade significantly reduced the proinflammatory responses and ameliorated arthritis development. CONCLUSIONS: OX40 acts as an alternative costimulator of CD4(+)CD28(−) T cells and plays a pathogenic role in autoimmune arthritic development, suggesting that it is a potential target for immunomodulatory therapy of RA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13075-017-1261-9) contains supplementary material, which is available to authorized users. BioMed Central 2017-03-21 2017 /pmc/articles/PMC5359925/ /pubmed/28320444 http://dx.doi.org/10.1186/s13075-017-1261-9 Text en © The Author(s). 2017 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 Article
Jiang, Juean
Liu, Cuiping
Liu, Mi
Shen, Yu
Hu, Xiaohan
Wang, Qin
Wu, Jian
Wu, Min
Fang, Qi
Zhang, Xueguang
OX40 signaling is involved in the autoactivation of CD4(+)CD28(−) T cells and contributes to the pathogenesis of autoimmune arthritis
title OX40 signaling is involved in the autoactivation of CD4(+)CD28(−) T cells and contributes to the pathogenesis of autoimmune arthritis
title_full OX40 signaling is involved in the autoactivation of CD4(+)CD28(−) T cells and contributes to the pathogenesis of autoimmune arthritis
title_fullStr OX40 signaling is involved in the autoactivation of CD4(+)CD28(−) T cells and contributes to the pathogenesis of autoimmune arthritis
title_full_unstemmed OX40 signaling is involved in the autoactivation of CD4(+)CD28(−) T cells and contributes to the pathogenesis of autoimmune arthritis
title_short OX40 signaling is involved in the autoactivation of CD4(+)CD28(−) T cells and contributes to the pathogenesis of autoimmune arthritis
title_sort ox40 signaling is involved in the autoactivation of cd4(+)cd28(−) t cells and contributes to the pathogenesis of autoimmune arthritis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359925/
https://www.ncbi.nlm.nih.gov/pubmed/28320444
http://dx.doi.org/10.1186/s13075-017-1261-9
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