Epstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.

Epstein-Barr virus (EBV), a lymphomagenic human herpesvirus, colonises the host through polyclonal B cell-growth-transforming infections yet establishes persistence only in IgD⁺ CD27⁺ non-switched memory (NSM) and IgD⁻ CD27⁺ switched memory (SM) B cells, not in IgD⁺ CD27⁻ naïve (N) cells. How this s...

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Autores principales:	Emily Heath, Noelia Begue-Pastor, Sridhar Chaganti, Debbie Croom-Carter, Claire Shannon-Lowe, Dieter Kube, Regina Feederle, Henri-Jacques Delecluse, Alan B Rickinson, Andrew I Bell
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ed4f30f2a0934f5cad9fcf65c29bad6a
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spelling	oai:doaj.org-article:ed4f30f2a0934f5cad9fcf65c29bad6a2021-11-18T06:04:26ZEpstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.1553-73661553-737410.1371/journal.ppat.1002697https://doaj.org/article/ed4f30f2a0934f5cad9fcf65c29bad6a2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22589726/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Epstein-Barr virus (EBV), a lymphomagenic human herpesvirus, colonises the host through polyclonal B cell-growth-transforming infections yet establishes persistence only in IgD⁺ CD27⁺ non-switched memory (NSM) and IgD⁻ CD27⁺ switched memory (SM) B cells, not in IgD⁺ CD27⁻ naïve (N) cells. How this selectivity is achieved remains poorly understood. Here we show that purified N, NSM and SM cell preparations are equally transformable in vitro to lymphoblastoid cells lines (LCLs) that, despite upregulating the activation-induced cytidine deaminase (AID) enzyme necessary for Ig isotype switching and Ig gene hypermutation, still retain the surface Ig phenotype of their parental cells. However, both N- and NSM-derived lines remain inducible to Ig isotype switching by surrogate T cell signals. More importantly, IgH gene analysis of N cell infections revealed two features quite distinct from parallel mitogen-activated cultures. Firstly, following 4 weeks of EBV-driven polyclonal proliferation, individual clonotypes then become increasingly dominant; secondly, in around 35% cases these clonotypes carry Ig gene mutations which both resemble AID products and, when analysed in prospectively-harvested cultures, appear to have arisen by sequence diversification in vitro. Thus EBV infection per se can drive at least some naïve B cells to acquire Ig memory genotypes; furthermore, such cells are often favoured during an LCL's evolution to monoclonality. Extrapolating to viral infections in vivo, these findings could help to explain how EBV-infected cells become restricted to memory B cell subsets and why EBV-driven lymphoproliferative lesions, in primary infection and/or immunocompromised settings, so frequently involve clones with memory genotypes.Emily HeathNoelia Begue-PastorSridhar ChagantiDebbie Croom-CarterClaire Shannon-LoweDieter KubeRegina FeederleHenri-Jacques DelecluseAlan B RickinsonAndrew I BellPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 5, p e1002697 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Emily Heath Noelia Begue-Pastor Sridhar Chaganti Debbie Croom-Carter Claire Shannon-Lowe Dieter Kube Regina Feederle Henri-Jacques Delecluse Alan B Rickinson Andrew I Bell Epstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.
description	Epstein-Barr virus (EBV), a lymphomagenic human herpesvirus, colonises the host through polyclonal B cell-growth-transforming infections yet establishes persistence only in IgD⁺ CD27⁺ non-switched memory (NSM) and IgD⁻ CD27⁺ switched memory (SM) B cells, not in IgD⁺ CD27⁻ naïve (N) cells. How this selectivity is achieved remains poorly understood. Here we show that purified N, NSM and SM cell preparations are equally transformable in vitro to lymphoblastoid cells lines (LCLs) that, despite upregulating the activation-induced cytidine deaminase (AID) enzyme necessary for Ig isotype switching and Ig gene hypermutation, still retain the surface Ig phenotype of their parental cells. However, both N- and NSM-derived lines remain inducible to Ig isotype switching by surrogate T cell signals. More importantly, IgH gene analysis of N cell infections revealed two features quite distinct from parallel mitogen-activated cultures. Firstly, following 4 weeks of EBV-driven polyclonal proliferation, individual clonotypes then become increasingly dominant; secondly, in around 35% cases these clonotypes carry Ig gene mutations which both resemble AID products and, when analysed in prospectively-harvested cultures, appear to have arisen by sequence diversification in vitro. Thus EBV infection per se can drive at least some naïve B cells to acquire Ig memory genotypes; furthermore, such cells are often favoured during an LCL's evolution to monoclonality. Extrapolating to viral infections in vivo, these findings could help to explain how EBV-infected cells become restricted to memory B cell subsets and why EBV-driven lymphoproliferative lesions, in primary infection and/or immunocompromised settings, so frequently involve clones with memory genotypes.
format	article
author	Emily Heath Noelia Begue-Pastor Sridhar Chaganti Debbie Croom-Carter Claire Shannon-Lowe Dieter Kube Regina Feederle Henri-Jacques Delecluse Alan B Rickinson Andrew I Bell
author_facet	Emily Heath Noelia Begue-Pastor Sridhar Chaganti Debbie Croom-Carter Claire Shannon-Lowe Dieter Kube Regina Feederle Henri-Jacques Delecluse Alan B Rickinson Andrew I Bell
author_sort	Emily Heath
title	Epstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.
title_short	Epstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.
title_full	Epstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.
title_fullStr	Epstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.
title_full_unstemmed	Epstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.
title_sort	epstein-barr virus infection of naïve b cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/ed4f30f2a0934f5cad9fcf65c29bad6a
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Epstein-Barr virus infection of naïve B cells in vitro frequently selects clones with mutated immunoglobulin genotypes: implications for virus biology.

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