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Department of Pathology, Academic Hospital, Vrije Universiteit, Amsterdam, The Netherlands
In neoplastic cells of EBV-positive lymphoid malignancies latent
membrane protein (LMP1) is expressed. Because no adequate cellular
immune response can be detected against LMP1, we investigated whether
LMP1 had a direct effect on T lymphocyte activation. In this study we
show that nanogram amounts of purified recombinant LMP1 (rLMP1)
strongly suppresses activation of T cells. By sequence alignment two
sequences (LALLFWL and LLLLAL) in the first transmembrane domain of
LMP1 were identified showing strong homology to the immunosuppressive
domain (LDLLFL) of the retrovirus-encoded transmembrane protein p15E.
The effects of rLMP1 and LMP1-derived peptides were tested in T cell
proliferation and NK cytotoxicity assays and an Ag-induced IFN-
release enzyme-linked immunospot assay. LMP1 derived LALLFWL peptides
showed strong inhibition of T cell proliferation and NK cytotoxicity,
while acetylated LALLFWL peptides had an even stronger effect. In
addition, Ag-specific IFN- release was severely inhibited. To exert
immunosuppressive effects in vivo, LMP1 has to be excreted from the
cells. Indeed, LMP1 was detected in supernatant of EBV-positive B cell
lines (LCL), and differential centrifugation in combination with
Western blot analysis of the pellets indicated that LMP1 is probably
secreted by LCL in the form of exosomes. The amount of secreted LMP1 in
B cell cultures is well below the immunosuppressive level observed with
rLMP1. Our results demonstrate direct immunosuppressive properties of
LMP1 (fragments) and suggest that EBV-positive tumor cells may actively
secrete LMP1 and thus mediate immunosuppressive effects on
tumor-infiltrating lymphocytes. Moreover, we demonstrate, for the first
time, that transmembrane protein-mediated immunosuppression is not
solely restricted to RNA tumor viruses, but can also be found in DNA
tumor viruses.
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