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* Department of Pediatrics,
Department of Microbiology and Immunology,
Department of Molecular and Cellular Physiology, and
Department of Medicine, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, CA 94305
Hemopoietic stem cell-derived mature Langerhans-type dendritic cells (LC) are susceptible to productive infection by human CMV (HCMV). To investigate the impact of infection on this cell type, we examined HLA-DR biosynthesis and trafficking in mature LC cultures exposed to HCMV. We found decreased surface HLA-DR levels in viral Ag-positive as well as in Ag-negative mature LC. Inhibition of HLA-DR was independent of expression of unique short US2-US11 region gene products by HCMV. Indeed, exposure to UV-inactivated virus, but not to conditioned medium from infected cells, was sufficient to reduce HLA-DR on mature LC, implicating particle binding/penetration in this effect. Reduced surface levels reflected an altered distribution of HLA-DR because total cellular HLA-DR was not diminished. Accumulation of HLA-DR was not explained by altered cathepsin S activity. Mature, peptide-loaded HLA-DR molecules were retained within cells, as assessed by the proportion of SDS-stable HLA-DR dimers. A block in egress was implicated, as endocytosis of surface HLA-DR was not increased. Immunofluorescence microscopy corroborated the intracellular retention of HLA-DR and revealed markedly fewer HLA-DR-positive dendritic projections in infected mature LC. Unexpectedly, light microscopic analyses showed a dramatic loss of the dendrites themselves and immunofluorescence revealed that cytoskeletal elements crucial for the formation and maintenance of dendrites are disrupted in viral Ag-positive cells. Consistent with these dendrite effects, HCMV-infected mature LC exhibit markedly reduced chemotaxis in response to lymphoid chemokines. Thus, HCMV impedes MHC class II molecule trafficking, dendritic projections, and migration of mature LC. These changes likely contribute to the reduced activation of CD4+ T cells by HCMV-infected mature LC.
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1 This work was supported by Grant PO1 AI48212 from the National Institutes of Health (to E.D.M. and E.S.M.), Grant RO1 AI30363 (to E.S.M.), Medical Scientist Training Program Grant GM07365 from the National Institute of General Medical Sciences (to R.K.L.), Grant BU 1822/1-1 from the Deutsche Forschungsgemeinschaft (to T.B.), and a Walter V. and Idun Y. Berry Fellowship of Stanford University (to A.W.L.).
2 Current address: University of Western Ontario, London, Ontario, Canada.
3 Current address: DiscoveRx Corporation, Fremont, CA 94538.
4 Current address: Roche Biosciences, Palo Alto, CA 94304.
5 Address correspondence and reprint requests to Dr. Elizabeth D. Mellins, Department of Pediatrics, Stanford University School of Medicine, 269 Campus Drive, Center for Clinical Sciences Research Building, Room 2115c, Stanford, CA 94305-5164. E-mail address: mellins{at}stanford.edu
6 Abbreviations used in this paper: HCMV, human CMV; LC, Langerhans cell; dpi, days postinfection; MOI, multiplicity of infection; B-LCL, B lymphoblastoid cell line; MFI, mean fluorescence intensity; DC, dendritic cell; Cat S, cathepsin S; US, unique short.
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