The Importance of Exogenous Antigen in Priming the Human CD8+ T Cell Response: Lessons from the EBV Nuclear Antigen EBNA1

Abstract

Mouse models suggest that the processing of exogenous Ag by dendritic cells can be important for priming the CD8+ CTL response. To study the situation in humans, we have exploited the CTL response to EBV infection. In this context EBV expresses eight latent proteins, of which EBV-encoded nuclear Ag (EBNA) 3A, 3B, and 3C appear to be immunodominant for CTL responses, whereas another nuclear Ag, EBNA1, which is completely protected from endogenous presentation via the MHC class I pathway, is thought to induce responses rarely, if ever. Here, using EBNA1 peptides and/or EBNA1 protein-loaded dendritic cells as in vitro stimuli, we have identified memory CTL responses to HLA-B*3501, -B7, and -B53-restricted EBNA1 epitopes that can be as strong as those seen in immunodominant epitopes from the “conventionally processed” EBNA3 Ags. Furthermore, we used HLA-peptide tetramers to show that the primary response to one such EBNA1 epitope constituted up to 5% of the CD8+ T cells in infectious mononucleosis blood, the strongest latent Ag-specific response yet detected in this setting. We conclude that exogenous protein represents a significant source of Ag for priming the human CTL response.

Mini‐review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross‐priming and direct priming?

“…Similar observations have been made in many different viral infections, including vaccinia virus [5, 77,78], influenza virus [78] and Epstein-Barr virus (EBV) [79,80] infection. In the case of EBV-induced Burkitt's lymphoma, a glycine-alanine repeat domain in the EBNA1 protein, required to establish viral latency, completely blocks proteasome-dependent MHC class I processing in EBNA1-expressing cells.…”

“…In the case of EBV-induced Burkitt's lymphoma, a glycine-alanine repeat domain in the EBNA1 protein, required to establish viral latency, completely blocks proteasome-dependent MHC class I processing in EBNA1-expressing cells. Nonetheless EBNA1-specific CTL can be readily detected in EBV-infected individuals [79,80]. This can best be explained by crosspresentation and cross-priming.…”

“…This can best be explained by crosspresentation and cross-priming. Indeed DC readily process and present exogenously offered EBNA1 protein in MHC class I molecules [79,80].…”

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

“…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]. Moreover, detection of anti-EBNA IgG in seropositive individuals suggests need for CD4 help.…”

Autocensure de la protéine EBNA1 pour échapper à la reconnaissance immunitaire

“…Or, ce n'est pas le cas, car il est très difficile de détecter cette protéine EBNA1 dans les cellules infectées. De plus, une réponse T cytotoxique peut être induite contre des peptides d'EBNA1 par un mécanisme appelé cross presentation [4]. Ces cellules T peuvent reconnaître des molécules du CMH I chargées en peptides exogènes provenant de la protéine EBNA1 mais pas des molécules du CMH I présentant des peptides endogènes.…”