PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells

Abstract We have previously shown that OX40L/OX40 interaction is critical for TCR-independent selective proliferation of Foxp3+ Tregs, but not Foxp3− effector T-cells (Teff), when CD4+ T-cells are co-cultured with GM-CSF derived bone marrow dendritic cells (G-BMDCs). Events downstream of OX40L/OX40...

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Autores principales:	Khaled Alharshawi, Alejandra Marinelarena, Prabhakaran Kumar, Osama El-Sayed, Palash Bhattacharya, Zuoming Sun, Alan L. Epstein, Ajay V. Maker, Bellur S. Prabhakar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/57f641e5cbe94b2d983028a3edbd7fd1
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spelling	oai:doaj.org-article:57f641e5cbe94b2d983028a3edbd7fd12021-12-02T11:41:08ZPKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells10.1038/s41598-017-05254-82045-2322https://doaj.org/article/57f641e5cbe94b2d983028a3edbd7fd12017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05254-8https://doaj.org/toc/2045-2322Abstract We have previously shown that OX40L/OX40 interaction is critical for TCR-independent selective proliferation of Foxp3+ Tregs, but not Foxp3− effector T-cells (Teff), when CD4+ T-cells are co-cultured with GM-CSF derived bone marrow dendritic cells (G-BMDCs). Events downstream of OX40L/OX40 interaction in Tregs responsible for this novel mechanism are not understood. Earlier, OX40L/OX40 interaction has been shown to stimulate CD4+ T-cells through the formation of a signalosome involving TRAF2/PKC-Ѳ leading to NF-kB activation. In this study, using CD4+ T-cells from WT and OX40−/− mice we first established that OX40 mediated activation of NF-kB was critical for this Treg proliferation. Although CD4+ T-cells from PKC-Ѳ−/− mice were also defective in G-BMDC induced Treg proliferation ex vivo, this defect could be readily corrected by adding exogenous IL-2 to the co-cultures. Furthermore, by treating WT, OX40−/−, and PKC-Ѳ−/− mice with soluble OX40L we established that OX40L/OX40 interaction was required and sufficient to induce Treg proliferation in vivo independent of PKC-Ѳ status. Although PKC-Ѳ is dispensable for TCR-independent Treg proliferation per se, it is essential for optimum IL-2 production by Teff cells. Finally, our findings suggest that OX40L binding to OX40 likely results in recruitment of TRAF1 for downstream signalling.Khaled AlharshawiAlejandra MarinelarenaPrabhakaran KumarOsama El-SayedPalash BhattacharyaZuoming SunAlan L. EpsteinAjay V. MakerBellur S. PrabhakarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Khaled Alharshawi Alejandra Marinelarena Prabhakaran Kumar Osama El-Sayed Palash Bhattacharya Zuoming Sun Alan L. Epstein Ajay V. Maker Bellur S. Prabhakar PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells
description	Abstract We have previously shown that OX40L/OX40 interaction is critical for TCR-independent selective proliferation of Foxp3+ Tregs, but not Foxp3− effector T-cells (Teff), when CD4+ T-cells are co-cultured with GM-CSF derived bone marrow dendritic cells (G-BMDCs). Events downstream of OX40L/OX40 interaction in Tregs responsible for this novel mechanism are not understood. Earlier, OX40L/OX40 interaction has been shown to stimulate CD4+ T-cells through the formation of a signalosome involving TRAF2/PKC-Ѳ leading to NF-kB activation. In this study, using CD4+ T-cells from WT and OX40−/− mice we first established that OX40 mediated activation of NF-kB was critical for this Treg proliferation. Although CD4+ T-cells from PKC-Ѳ−/− mice were also defective in G-BMDC induced Treg proliferation ex vivo, this defect could be readily corrected by adding exogenous IL-2 to the co-cultures. Furthermore, by treating WT, OX40−/−, and PKC-Ѳ−/− mice with soluble OX40L we established that OX40L/OX40 interaction was required and sufficient to induce Treg proliferation in vivo independent of PKC-Ѳ status. Although PKC-Ѳ is dispensable for TCR-independent Treg proliferation per se, it is essential for optimum IL-2 production by Teff cells. Finally, our findings suggest that OX40L binding to OX40 likely results in recruitment of TRAF1 for downstream signalling.
format	article
author	Khaled Alharshawi Alejandra Marinelarena Prabhakaran Kumar Osama El-Sayed Palash Bhattacharya Zuoming Sun Alan L. Epstein Ajay V. Maker Bellur S. Prabhakar
author_facet	Khaled Alharshawi Alejandra Marinelarena Prabhakaran Kumar Osama El-Sayed Palash Bhattacharya Zuoming Sun Alan L. Epstein Ajay V. Maker Bellur S. Prabhakar
author_sort	Khaled Alharshawi
title	PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells
title_short	PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells
title_full	PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells
title_fullStr	PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells
title_full_unstemmed	PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells
title_sort	pkc-ѳ is dispensable for ox40l-induced tcr-independent treg proliferation but contributes by enabling il-2 production from effector t-cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/57f641e5cbe94b2d983028a3edbd7fd1
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PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells

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