Journal of Virology, June 2001, p. 5174-5181, Vol. 75, No. 11
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.11.5174-5181.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
1-Independent
Suppression of T-Cell Proliferation in Human Cytomegalovirus-Infected
Macrophage Cultures
Karolinska Institute, Division of Clinical Immunology, Huddinge Hospital, and Department of Biosciences, Novum, Stockholm, Sweden
Received 20 November 2000/Accepted 5 March 2001
After a primary infection, human cytomegalovirus (HCMV) establishes
lifelong latency in myeloid lineage cells, and the virus has developed
several mechanisms to avoid immune recognition and destruction of
infected cells. In this study, we show that HCMV utilizes two different
strategies to reduce the constitutive expression of HLA-DR, -DP, and
-DQ on infected macrophages and that infected macrophages are unable to
stimulate a specific CD4+ T-cell response. Downregulation
of the HLA class II molecules was observed in 90% of the donor samples
and occurred in two phases: at an early (1 day postinfection [dpi])
time point postinfection and at a late (4 dpi) time point
postinfection. The early inhibition of HLA class II expression and
antigen presentation was not dependent on active virus replication,
since UV-inactivated virus induced downregulation of HLA-DR and
inhibition of T-cell proliferation at 1 dpi. In contrast, the late
effect required virus replication and was dependent on the expression
of the HCMV unique short (US) genes US1 to -9 or US11 in 77% of the
samples. HCMV-treated macrophages were completely devoid of T-cell
stimulation capacity at 1 and 4 dpi. However, while downregulation of
HLA class II expression was rather mild, a 66 to 90% reduction in
proliferative T-cell response was observed. This discrepancy was due to
undefined soluble factors produced in HCMV-infected cell cultures,
which did not include interleukin-10 and transforming growth factor
1. These results suggest that HCMV reduces expression of HLA class
II molecules on HCMV-infected macrophages and inhibits T-cell
proliferation by different distinct pathways.
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