Abstracts (complete list) - Wissenschaft Online

Jan Diekmann, Olaf Beck, Georg Rauser, Hansjörg Schild, Hermann Einsele, Max S.
Topp
Different mechanisms contribute to the immune evasion of
Epstein-Barr virus latent membrane protein 1
Epstein-Barr virus (EBV) infection is associated with several pathogenic conditions such
as nasopharyngeal carcinoma, NK and T cell lymphomas and Hodgkin`s disease, which
all express latency type II proteins including the latent membrane proteins 1 and 2
(LMP1/2). Both LMP1 and 2 have been suggested to represent targets for
immunotherapy with antigen-specific CD8+ T cells. After generation of HLA-A*0201
restricted CD8+ T cells specific for the YLLEMLWRL and CLGGLLTMV epitopes from the
LMP1 and LMP2, respectively, we could show, that only the LMP2-specific CD8+ T cells
were able to lyse antigen-expressing target cells.
In order to investigate the mechanism responsible for the observed unresponsiveness of
the LMP1-specific CD8+ T cells against LMP1-expressing target cells, the targets were
treated with the proteasomal inhibitors MG132 and Epoxomicin. Both inhibitors could
restore the immunogenicity of the target cells towards the LMP1-specific CD8+ T cells,
suggesting, that blocking of the proteasome prevents destruction of the epitope and the
same time enables processing through other proteases. Blocking of the proteasome by
siRNA targeting of POMP greatly enhanced epitope-specific activation of the T cells
emphasising, that prevention of proteasomal processing of LMP1 allows sufficient
generation of viral epitopes.
Alternatively, genetic truncation of the cytosolic part and the first four transmembrane
regions of LMP1 could also restore good target recognition, stressing that LMP1 may
contain sequences for selective inhibition of cytosolic proteases such as tripeptidyl
peptidase II (TPPII) or thimet oligopeptidase (ThOP).
These findings indicate, that the LMP1 epitope YLLEMLWRL is prevented from MHC-I
presentation by distruction through the proteasome and inhibitory influences of the Nterminal
transmembrane domains of the protein. We propose that this novel function
may represent an additional immune evasion strategy employed by Epstein-Barr virus.