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Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway

Transient suppression of B cell function often accompanies acute viral infection. However, the molecular signaling circuitry that enforces this hyporesponsiveness is undefined. In this study, experiments identify up-regulation of the inositol phosphatase PTEN (phosphatase and tensin homolog) as prim...

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Autores principales: Getahun, Andrew, Wemlinger, Scott M., Rudra, Pratyaydipta, Santiago, Mario L., van Dyk, Linda F., Cambier, John C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379973/
https://www.ncbi.nlm.nih.gov/pubmed/28341640
http://dx.doi.org/10.1084/jem.20160972
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author Getahun, Andrew
Wemlinger, Scott M.
Rudra, Pratyaydipta
Santiago, Mario L.
van Dyk, Linda F.
Cambier, John C.
author_facet Getahun, Andrew
Wemlinger, Scott M.
Rudra, Pratyaydipta
Santiago, Mario L.
van Dyk, Linda F.
Cambier, John C.
author_sort Getahun, Andrew
collection PubMed
description Transient suppression of B cell function often accompanies acute viral infection. However, the molecular signaling circuitry that enforces this hyporesponsiveness is undefined. In this study, experiments identify up-regulation of the inositol phosphatase PTEN (phosphatase and tensin homolog) as primarily responsible for defects in B lymphocyte migration and antibody responses that accompany acute viral infection. B cells from mice acutely infected with gammaherpesvirus 68 are defective in BCR- and CXCR4-mediated activation of the PI3K pathway, and this, we show, is associated with increased PTEN expression. This viral infection-induced PTEN overexpression appears responsible for the suppression of antibody responses observed in infected mice because PTEN deficiency or expression of a constitutively active PI3K rescued function of B cells in infected mice. Conversely, induced overexpression of PTEN in B cells in uninfected mice led to suppression of antibody responses. Finally, we demonstrate that PTEN up-regulation is a common mechanism by which infection induces suppression of antibody responses. Collectively, these findings identify a novel role for PTEN during infection and identify regulation of the PI3K pathway, a mechanism previously shown to silence autoreactive B cells, as a key physiological target to control antibody responses.
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spelling pubmed-53799732017-10-03 Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway Getahun, Andrew Wemlinger, Scott M. Rudra, Pratyaydipta Santiago, Mario L. van Dyk, Linda F. Cambier, John C. J Exp Med Research Articles Transient suppression of B cell function often accompanies acute viral infection. However, the molecular signaling circuitry that enforces this hyporesponsiveness is undefined. In this study, experiments identify up-regulation of the inositol phosphatase PTEN (phosphatase and tensin homolog) as primarily responsible for defects in B lymphocyte migration and antibody responses that accompany acute viral infection. B cells from mice acutely infected with gammaherpesvirus 68 are defective in BCR- and CXCR4-mediated activation of the PI3K pathway, and this, we show, is associated with increased PTEN expression. This viral infection-induced PTEN overexpression appears responsible for the suppression of antibody responses observed in infected mice because PTEN deficiency or expression of a constitutively active PI3K rescued function of B cells in infected mice. Conversely, induced overexpression of PTEN in B cells in uninfected mice led to suppression of antibody responses. Finally, we demonstrate that PTEN up-regulation is a common mechanism by which infection induces suppression of antibody responses. Collectively, these findings identify a novel role for PTEN during infection and identify regulation of the PI3K pathway, a mechanism previously shown to silence autoreactive B cells, as a key physiological target to control antibody responses. The Rockefeller University Press 2017-04-03 /pmc/articles/PMC5379973/ /pubmed/28341640 http://dx.doi.org/10.1084/jem.20160972 Text en © 2017 Getahun 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 Research Articles
Getahun, Andrew
Wemlinger, Scott M.
Rudra, Pratyaydipta
Santiago, Mario L.
van Dyk, Linda F.
Cambier, John C.
Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway
title Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway
title_full Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway
title_fullStr Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway
title_full_unstemmed Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway
title_short Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway
title_sort impaired b cell function during viral infections due to pten-mediated inhibition of the pi3k pathway
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379973/
https://www.ncbi.nlm.nih.gov/pubmed/28341640
http://dx.doi.org/10.1084/jem.20160972
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