Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells.
Exosomes, nano-sized membrane vesicles, are released by various cells and are found in many human body fluids. They are active players in intercellular communication and have immune-suppressive, immune-regulatory, and immune-stimulatory functions. EBV is a ubiquitous human herpesvirus that is associated with various lymphoid and epithelial malignancies. EBV infection of B cells in vitro induces the release of exosomes that harbor the viral latent membrane protein 1 (LMP1). LMP1 per se mimics CD40 signaling and induces proliferation of B lymphocytes and T cell-independent class-switch recombination. Constitutive LMP1 signaling within B cells is blunted through the shedding of LMP1 via exosomes. In this study, we investigated the functional effect of exosomes derived from the DG75 Burkitt's lymphoma cell line and its sublines (LMP1 transfected and EBV infected), with the hypothesis that they might mimic exosomes released during EBV-associated diseases. We show that exosomes released during primary EBV infection of B cells harbored LMP1, and similar levels were detected in exosomes from LMP1-transfected DG75 cells. DG75 exosomes efficiently bound to human B cells within PBMCs and were internalized by isolated B cells. In turn, this led to proliferation, induction of activation-induced cytidine deaminase, and the production of circle and germline transcripts for IgG1 in B cells. Finally, exosomes harboring LMP1 enhanced proliferation and drove B cell differentiation toward a plasmablast-like phenotype. In conclusion, our results suggest that exosomes released from EBV-infected B cells have a stimulatory capacity and interfere with the fate of human B cells.
Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden; cindy.gutzeit@mssm.edu.
Cindy
C
Gutzeit
Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
Noemi
N
Nagy
Institut Hospital del la Mar d'Investigacions Mèdiques, 08003 Barcelona, Spain; and.
Maurizio
M
Gentile
Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden.
Katarina
K
Lyberg
Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden;
Janine
J
Gumz
Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden;
Helen
H
Vallhov
Institut Hospital del la Mar d'Investigacions Mèdiques, 08003 Barcelona, Spain; and.
Irene
I
Puga
Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden;
Eva
E
Klein
Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden;
Susanne
S
Gabrielsson
Institut Hospital del la Mar d'Investigacions Mèdiques, 08003 Barcelona, Spain; and.
Andrea
A
Cerutti
Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, 17177 Stockholm, Sweden;
Annika
A
Scheynius
D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002051:Burkitt Lymphoma / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055354:Exosomes / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D008297:Male; D014763:Viral Matrix Proteins / Q000276:immunology
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins