Bystander inhibition of humoral immune responses by Epstein–Barr virus LMP1

Abstract

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), which mimics a constitutively active receptor, is required for viral transformation of primary B cells. LMP1 is expressed in EBV-infected germinal center (GC) B cells of immunocompetent individuals, suggesting that it may contribute to persistent EBV infection. In this study, we generated and analyzed mice that expressed LMP1 under the control of the CD19 or activation-induced cytidine deaminase (AID) promoter. Expression of LMP1 induced activation of B cells but severely inhibited their differentiation into antibody-secreting cells (ASCs) in vitro and GC B cells in vivo. LMP1-expressing (LMP1+) B cells not only suppressed the functions of wild-type (WT) B cells in in vitro co-culture, but also blocked differentiation of WT B cells into GC B cells and ASCs in immunized bone marrow chimeric mice. Microarray analysis revealed that the gene encoding indoleamine 2,3-dioxygenase 1 (IDO1), a major enzyme involved in the tryptophan metabolic process, was highly induced by LMP1. Either inhibition of IDO1 activity by methyl-l-tryptophan or knockout of Ido1 in LMP1+ B cells could rescue WT B cells from such suppression. IDO1-induced tryptophan consumption and production of tryptophan metabolites appeared to be responsible for inhibition of B-cell function. We conclude that LMP1 expression in antigen-committed B cells not only directly impairs GC B-cell differentiation, but also indirectly inhibits the functions of neighboring B cells, resulting in suppression of humoral immune responses. Such bystander inhibition by LMP1+ B cells may contribute to immune evasion by EBV.

Immunosuppressive Tumor Microenvironment and Immunotherapy of Epstein–Barr Virus-Associated Malignancies

“…Moreover, the number of infiltrated B cells varies greatly and they mostly reside in the stroma [ 76 ]. LMP1 can block the differentiation of B cells into antibody-secreting cells [ 77 ] through the upregulation of indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 can also inhibit B cell function, thus further suppressing immune responses [ 77 ].…”

“…LMP1 can block the differentiation of B cells into antibody-secreting cells [ 77 ] through the upregulation of indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 can also inhibit B cell function, thus further suppressing immune responses [ 77 ]. It is reported that EBV-infected cells can express miRNA-21 and then induce the expression of IL-10 in naive B cells, which is capable of suppressing CD8+ T cell activities [ 78 ].…”

Metabolic Regulation of Immune Responses to Mycobacterium tuberculosis: A Spotlight on L-Arginine and L-Tryptophan Metabolism

“…In mice, B cell IDO1 is upregulated following T cell-independent antigen immunization, leading to impaired antibody production ( 233 ). Further, B cells expressing Epstein-Barr virus latent membrane protein 1 (LMP1) suppressed antibody secretion in LMP1-negative B cells, which was reversed upon 1-MT treatment ( 234 ). In a mouse model of Helicobacter felis -induced gastritis, Ido1 -/- mice displayed decreased B cell frequency within the gastric mucosa ( 235 ).…”

Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma

“…LMP1 in exosomes effectively stimulates MAPK and Akt activation, promotes cell proliferation and inhibits host immunity ( 119 ). In addition, LMP1 can induce B cell activation but severely inhibits B cell differentiation into antibody-secreting cells (ASCs) ( 120 ).…”