title: Human cytomegalovirus pUL10 interacts with leukocytes and impairs TCR-mediated T-cell activation.
abstract: Human cytomegalovirus (HCMV) is known to exert suppressive effects on the host immune system through expression of various viral genes, thus directly and indirectly affecting antiviral immunity of the infected individuals. We report here that HCMV UL10 encodes a protein (pUL10) with immunosuppressive properties. UL10 has been classified as a member of the HCMV RL11 gene family. Although pUL10 is known to be dispensable for viral replication in cultured cells, its amino-acid sequence is well conserved among different HCMV isolates, suggesting that the protein has a crucial role in viral survival in the host environment. We show that pUL10 is cleaved from the cell surface of fibroblasts as well as epithelial cells and interacts with a cellular receptor ubiquitously expressed on the surface of human leukocytes, demonstrated by ex vivo cell-based assays and flow cytometric analyses on both lymphoid cell lines and primary blood cells. Furthermore, preincubation of peripheral blood mononuclear cells with purified pUL10 ectodomain results in significantly impaired proliferation and substantially reduced pro-inflammatory cytokine production, in particular in CD4+T cells upon in vitro T-cell stimulation. The inhibitory effect of pUL10 is also observed on antigen receptor-mediated intracellular tyrosine phosphorylation in a T-cell line. Based on these observations, we suggest that pUL10 is a newly identified immunomodulatory protein encoded by HCMV. Further elucidation of interactions between pUL10 and the host immune system during HCMV may contribute to finding ways towards new therapies for HCMV infection.
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bruno
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Cortese
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Monda
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Gentile
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Calò
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavetti
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Luisanna
authors.initials: L
authors.lastname: Zedda
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Piccioli
authors.affiliation: Research, GSK Vaccines, Cambridge, MA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Schaefer
authors.affiliation: Department of Biology, University of Naples 'Federico II', Naples, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Notomista
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Maione
authors.affiliation: Research, GSK Vaccines, Cambridge, MA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfì
authors.affiliation: Research, GSK Vaccines, Siena, Italy.|Department of Biology, University of Naples 'Federico II', Naples, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Merola
authors.affiliation: Research, GSK Vaccines, Siena, Italy.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Uematsu
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D036022:Capsid Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D036022:Capsid Proteins; D016207:Cytokines; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; C000618375:pUL103 tegument protein, Human Cytomegalovirus