Epstein-Barr Virus Infection of Naïve B Cells In Vitro Frequently Selects Clones with Mutated Immunoglobulin Genotypes: Implications for Virus Biology

PLoS Pathogens

Dieter Kube¹  Henri-Jacques Delecluse²  Andrew I. Bell²  Claire Shannon-Lowe³  Alan B. Rickinson³  Noelia Begue-Pastor³  Regina Feederle³  Emily Heath³  Debbie Croom-Carter³  Sridhar Chaganti³ 

[1] Department of Haematology and Oncology, Georg August University Göttingen, Göttingen, Germany;Department of Virus-Associated Tumours, DKFZ, Heidelberg, Germany;School of Cancer Sciences, College of Medicine and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom

关键词: B cells;    Memory B cells;    Polymerase chain reaction;    Sequence analysis;    Cloning;    Mutation;    Epstein-Barr virus;    T cells;   

DOI  :  10.1371/journal.ppat.1002697

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY