Human Cd4+ T Lymphocytes Consistently Respond to the Latent Epstein-Barr Virus Nuclear Antigen Ebna1

Abstract

The Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1 is critical for the persistence of the viral episome in replicating EBV-transformed human B cells. Therefore, all EBV-induced tumors express this foreign antigen. However, EBNA1 is invisible to CD8+ cytotoxic T lymphocytes because its Gly/Ala repeat domain prevents proteasome-dependent processing for presentation on major histocompatibility complex (MHC) class I. We now describe that CD4+ T cells from healthy adults are primed to EBNA1. In fact, among latent EBV antigens that stimulate CD4+ T cells, EBNA1 is preferentially recognized. We present evidence that the CD4+ response may provide a protective role, including interferon γ secretion and direct cytolysis after encounter of transformed B lymphocyte cell lines (B-LCLs). Dendritic cells (DCs) process EBNA1 from purified protein and from MHC class II–mismatched, EBNA1-expressing cells including B-LCLs. In contrast, B-LCLs and Burkitt's lymphoma lines likely present EBNA1 after endogenous processing, as their capacity to cross-present from exogenous sources is weak or undetectable. By limiting dilution, there is a tight correlation between the capacity of CD4+ T cell lines to recognize autologous B-LCL–expressing EBNA1 and DCs that have captured EBNA1. Therefore, CD4+ T cells can respond to the EBNA1 protein that is crucial for EBV persistence. We suggest that this immune response is initiated in vivo by DCs that present EBV-infected B cells, and that EBNA1-specific CD4+ T cell immunity be enhanced to prevent and treat EBV-associated malignancies.

Deiminated Epstein‐Barr virus nuclear antigen 1 is a target of anti–citrullinated protein antibodies in rheumatoid arthritis

“…EBNA-1-specific CD4ϩ T cells (45,46), mainly of the Th1 phenotype (47), have recently been detected in healthy EBV carriers and may provide help for the production of antibodies directed to the different epitopes of this protein. In the presence of a higher EBV load, events such as apoptosis, infection, damage, or any stimulus involving calcium influx may activate PAD, which is highly expressed in RA synovia (48,49), and induce the deimination of different proteins, including viral proteins.…”

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

“…EBV nuclear antigen 1 (EBNA-1) is a latent antigen that is invariably expressed in all EBV-infected proliferating cells [16] and associated malignancies [17], being crucial for viral persistence by acting as replication and transcription factor [18], without viral particle formation. EBNA-1 is an immunodominant latent target of EBVspecific CD4 1 T cells [19,20]. Although it has been described in the past to escape from recognition by CD8 1 T cells due to Gly/Ala repeated domains preventing proteasome-dependent processing for presentation on MHC class I [21], more recent studies revealed the existence of EBNA-1-specific CD8 1 T cells [15,22,23].…”

Immune surveillance of intracellular pathogens via autophagy

“…Subsequently, presentation of endogenous proteins on MHC class II has been described for a number of other viral antigens [28][29][30][31] as well as self-antigens, 21,32-34 model antigens, [35][36][37][38][39][40] and tumor antigens 41,42 (Table 2). On the basis of these findings, four endogenous MHC class II processing pathways can be postulated [43][44][45] (Figure 1).…”

“…47 In addition to these proteasome-dependent pathways, cytosolic and nuclear proteins can also be processed by a proteasome-and TAPindependent pathway: This fourth pathway involves the direct import of cytosolic/nuclear proteins (e.g. the EBV nuclear antigen 1 (EBNA1) 30,31 ) into endosomes/lysosomes and is in part mediated by autophagy. The latter three pathways (processing of cytosolic or nuclear proteins by proteasomedependent or -independent mechanisms) contribute more than 20% of endogenous MHC class II ligands.…”