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Epstein-barr virus nuclear antigen 1: from immunologically invisible to a promising T cell target.

Münz C - J. Exp. Med. (2004)

Bottom Line: Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)--the one EBV antigen that is expressed in all EBV-associated malignancies--has long been thought to go undetected by the cell-mediated immune system.However, recent studies show that EBNA1 can be presented to both CD4+ and CD8+ T cells, making it a potential new target for immunotherapy of EBV-related cancers.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Viral Immunobiology, The Rockefeller University, 1230 York Ave., New York, NY 10021, USA. munzc@rockefeller.edu

ABSTRACT
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)--the one EBV antigen that is expressed in all EBV-associated malignancies--has long been thought to go undetected by the cell-mediated immune system. However, recent studies show that EBNA1 can be presented to both CD4+ and CD8+ T cells, making it a potential new target for immunotherapy of EBV-related cancers.

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Related in: MedlinePlus

Suggested antigen processing pathways of EBNA1. (A) Defective ribosomal products (DRiPs) of EBNA1 are degraded by the proteasome for MHC class I presentation (endogenous MHC class I antigen processing). (B) Full-length EBNA1 is not degraded by the proteasome and might be the source of MHC class II ligands (endogenous MHC class II antigen processing). (C) EBNA1 released by dying EBV-transformed B cells is taken up by APCs and presented for CD4+ and CD8+ T cell priming (exogenous MHC class I and II antigen processing).
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fig1: Suggested antigen processing pathways of EBNA1. (A) Defective ribosomal products (DRiPs) of EBNA1 are degraded by the proteasome for MHC class I presentation (endogenous MHC class I antigen processing). (B) Full-length EBNA1 is not degraded by the proteasome and might be the source of MHC class II ligands (endogenous MHC class II antigen processing). (C) EBNA1 released by dying EBV-transformed B cells is taken up by APCs and presented for CD4+ and CD8+ T cell priming (exogenous MHC class I and II antigen processing).

Mentions: The three JEM papers on EBNA1-specific CD8+ T cells (19–21) also contain interesting information on the antigen processing and degradation of EBNA1. It was noted earlier that full-length EBNA1 is very stable with a half-life >20 h in B cell lines (10), but deletion of the Gly-Ala repeat domain (ΔGA) lowers EBNA1's half-life substantially (23). Degradation of the short-lived EBNA1ΔGA variant is proteasome dependent, whereas the degradation of long-lived full-length EBNA1 is proteasome independent (10). In the study by Tellam et al., the authors demonstrate that the half-life of full-length EBNA1 depends on the cellular background: it is reduced to 4 h in primary epithelial cell lines, but EBNA1 degradation remains insensitive to proteasome inhibition as in EBV-transformed B cells (21). By contrast, in all three studies CD8+ T cell recognition is inhibited by various proteasome inhibitors (19–21). These data suggest that EBNA1-derived CD8+ T cell epitopes are not derived from full-length EBNA1 but from proteins that are prematurely truncated during translation or mal-folded after translation (known as defective ribosomal products or DRiPs). These DRiPs are preferentially degraded by proteasomes for MHC class I presentation (Fig. 1) (24). Indeed, Voo et al. showed that CD8+ T cell recognition of EBNA1 can be rapidly blocked by ementine, an irreversible inhibitor of protein biosynthesis (19). Along the same lines, Tellam et al. report that they can block EBNA1-specific CD8+ T cell recognition of LCLs by another protein biosynthesis inhibitor, cyclohexamide (21). Since, most EBNA1-derived CD8+ T cell epitopes are COOH-terminal of the Gly-Ala repeat domain, the question remains why this domain cannot prevent DRiP degradation by the proteasome. The study by Voo et al. offers a possible answer to this dilemma. They report that EBNA1-derived CD8+ T cell epitope presentation is not only dependent on proteasome-mediated proteolysis but also on serine protease degradation (19). Preprocessing of DRiPs by a serine protease could separate the CD8+ T cell epitopes from the Gly-Ala repeat domain and make them accessible for proteasome degradation.


Epstein-barr virus nuclear antigen 1: from immunologically invisible to a promising T cell target.

Münz C - J. Exp. Med. (2004)

Suggested antigen processing pathways of EBNA1. (A) Defective ribosomal products (DRiPs) of EBNA1 are degraded by the proteasome for MHC class I presentation (endogenous MHC class I antigen processing). (B) Full-length EBNA1 is not degraded by the proteasome and might be the source of MHC class II ligands (endogenous MHC class II antigen processing). (C) EBNA1 released by dying EBV-transformed B cells is taken up by APCs and presented for CD4+ and CD8+ T cell priming (exogenous MHC class I and II antigen processing).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211815&req=5

fig1: Suggested antigen processing pathways of EBNA1. (A) Defective ribosomal products (DRiPs) of EBNA1 are degraded by the proteasome for MHC class I presentation (endogenous MHC class I antigen processing). (B) Full-length EBNA1 is not degraded by the proteasome and might be the source of MHC class II ligands (endogenous MHC class II antigen processing). (C) EBNA1 released by dying EBV-transformed B cells is taken up by APCs and presented for CD4+ and CD8+ T cell priming (exogenous MHC class I and II antigen processing).
Mentions: The three JEM papers on EBNA1-specific CD8+ T cells (19–21) also contain interesting information on the antigen processing and degradation of EBNA1. It was noted earlier that full-length EBNA1 is very stable with a half-life >20 h in B cell lines (10), but deletion of the Gly-Ala repeat domain (ΔGA) lowers EBNA1's half-life substantially (23). Degradation of the short-lived EBNA1ΔGA variant is proteasome dependent, whereas the degradation of long-lived full-length EBNA1 is proteasome independent (10). In the study by Tellam et al., the authors demonstrate that the half-life of full-length EBNA1 depends on the cellular background: it is reduced to 4 h in primary epithelial cell lines, but EBNA1 degradation remains insensitive to proteasome inhibition as in EBV-transformed B cells (21). By contrast, in all three studies CD8+ T cell recognition is inhibited by various proteasome inhibitors (19–21). These data suggest that EBNA1-derived CD8+ T cell epitopes are not derived from full-length EBNA1 but from proteins that are prematurely truncated during translation or mal-folded after translation (known as defective ribosomal products or DRiPs). These DRiPs are preferentially degraded by proteasomes for MHC class I presentation (Fig. 1) (24). Indeed, Voo et al. showed that CD8+ T cell recognition of EBNA1 can be rapidly blocked by ementine, an irreversible inhibitor of protein biosynthesis (19). Along the same lines, Tellam et al. report that they can block EBNA1-specific CD8+ T cell recognition of LCLs by another protein biosynthesis inhibitor, cyclohexamide (21). Since, most EBNA1-derived CD8+ T cell epitopes are COOH-terminal of the Gly-Ala repeat domain, the question remains why this domain cannot prevent DRiP degradation by the proteasome. The study by Voo et al. offers a possible answer to this dilemma. They report that EBNA1-derived CD8+ T cell epitope presentation is not only dependent on proteasome-mediated proteolysis but also on serine protease degradation (19). Preprocessing of DRiPs by a serine protease could separate the CD8+ T cell epitopes from the Gly-Ala repeat domain and make them accessible for proteasome degradation.

Bottom Line: Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)--the one EBV antigen that is expressed in all EBV-associated malignancies--has long been thought to go undetected by the cell-mediated immune system.However, recent studies show that EBNA1 can be presented to both CD4+ and CD8+ T cells, making it a potential new target for immunotherapy of EBV-related cancers.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Viral Immunobiology, The Rockefeller University, 1230 York Ave., New York, NY 10021, USA. munzc@rockefeller.edu

ABSTRACT
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)--the one EBV antigen that is expressed in all EBV-associated malignancies--has long been thought to go undetected by the cell-mediated immune system. However, recent studies show that EBNA1 can be presented to both CD4+ and CD8+ T cells, making it a potential new target for immunotherapy of EBV-related cancers.

Show MeSH
Related in: MedlinePlus