Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity

Abstract In vitro induced human regulatory T cells (iTregs) have demonstrated in vivo therapeutic utility, but pathways regulating their function have not been elucidated. Here, we report that human iTregs generated in vitro from naïve cord blood cells preferentially recruit Disc large homolog 1 (Dl...

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Autores principales:	Alexandra Zanin-Zhorov, Sudha Kumari, Keli L. Hippen, Sarah C. Merkel, Margaret L. MacMillan, Bruce R. Blazar, Michael L. Dustin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e68bbe646c9d458cb1c2346218358f5d
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spelling	oai:doaj.org-article:e68bbe646c9d458cb1c2346218358f5d2021-12-02T15:05:47ZHuman in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity10.1038/s41598-017-04053-52045-2322https://doaj.org/article/e68bbe646c9d458cb1c2346218358f5d2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04053-5https://doaj.org/toc/2045-2322Abstract In vitro induced human regulatory T cells (iTregs) have demonstrated in vivo therapeutic utility, but pathways regulating their function have not been elucidated. Here, we report that human iTregs generated in vitro from naïve cord blood cells preferentially recruit Disc large homolog 1 (Dlgh1) and exclude protein kinase C (PKC)-θ from immunological synapses formed on supported lipid bilayers with laterally mobile ICAM-1 and anti-CD3 mAb. Also, iTregs display elevated Dlgh1 overall and Dlgh1-dependent p38 phosphorylation, higher levels of phosphatase and tensin homolog (PTEN), and diminished Akt phosphorylation. Pharmacological interruption of PKC-θ increases and Dlgh1 silencing decreases the ability of iTregs to suppress interferon-γ production by CD4+CD25− effector T cells (Teff). Comparison with expanded cord blood-derived CD4+CD25hi tTreg and expanded Teffs from the same donors indicate that iTreg are intermediate between expanded CD4+CD25hi tTregs and Teffs, whereas modulation of suppressive activities by PKC-θ and Dlgh1 signaling pathways are shared.Alexandra Zanin-ZhorovSudha KumariKeli L. HippenSarah C. MerkelMargaret L. MacMillanBruce R. BlazarMichael L. DustinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alexandra Zanin-Zhorov Sudha Kumari Keli L. Hippen Sarah C. Merkel Margaret L. MacMillan Bruce R. Blazar Michael L. Dustin Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity
description	Abstract In vitro induced human regulatory T cells (iTregs) have demonstrated in vivo therapeutic utility, but pathways regulating their function have not been elucidated. Here, we report that human iTregs generated in vitro from naïve cord blood cells preferentially recruit Disc large homolog 1 (Dlgh1) and exclude protein kinase C (PKC)-θ from immunological synapses formed on supported lipid bilayers with laterally mobile ICAM-1 and anti-CD3 mAb. Also, iTregs display elevated Dlgh1 overall and Dlgh1-dependent p38 phosphorylation, higher levels of phosphatase and tensin homolog (PTEN), and diminished Akt phosphorylation. Pharmacological interruption of PKC-θ increases and Dlgh1 silencing decreases the ability of iTregs to suppress interferon-γ production by CD4+CD25− effector T cells (Teff). Comparison with expanded cord blood-derived CD4+CD25hi tTreg and expanded Teffs from the same donors indicate that iTreg are intermediate between expanded CD4+CD25hi tTregs and Teffs, whereas modulation of suppressive activities by PKC-θ and Dlgh1 signaling pathways are shared.
format	article
author	Alexandra Zanin-Zhorov Sudha Kumari Keli L. Hippen Sarah C. Merkel Margaret L. MacMillan Bruce R. Blazar Michael L. Dustin
author_facet	Alexandra Zanin-Zhorov Sudha Kumari Keli L. Hippen Sarah C. Merkel Margaret L. MacMillan Bruce R. Blazar Michael L. Dustin
author_sort	Alexandra Zanin-Zhorov
title	Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity
title_short	Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity
title_full	Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity
title_fullStr	Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity
title_full_unstemmed	Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity
title_sort	human in vitro-induced regulatory t cells display dlgh1 dependent and pkc-θ restrained suppressive activity
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e68bbe646c9d458cb1c2346218358f5d
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Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity

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