title: Cytomegalovirus encodes a positive regulator of antigen presentation.
abstract: Murine cytomegalovirus encodes three regulators of antigen presentation to antiviral CD8 T cells. According to current paradigms, all three regulators are committed to the inhibition of the presentation of antigenic peptides. Whereas m152/gp40 catalyzes the retention of peptide-loaded major histocompatibility complex (MHC) class I molecules in a cis-Golgi compartment, m06/gp48 binds stably to class I molecules and directs them into the cellular cargo-sorting pathway of lysosomal degradation. Regulator m04/gp34 also binds stably to class I molecules, but unlike m152 and m06, it does not downmodulate MHC class I cell surface expression. It has entered the literature as a direct inhibitor of T-cell recognition of the MHC-peptide complex at the cell surface. In this work, we have studied the presentation of antigenic viral peptides in cells infected with a comprehensive set of mutant viruses expressing the three regulators separately as well as in all possible combinations. The results redefine m04 as a positive regulator dedicated to the facilitation of antigen presentation. When expressed alone, it did not inhibit T-cell recognition, and when expressed in the presence of m152, it restored antigen presentation by antagonizing the inhibitory function of m152. Its intrinsic positive function, however, was antagonized and even slightly overcompensated for by the negative regulator m06. In an adoptive cell transfer model, the opposing forces of the three regulators were found to govern immune surveillance in the infected host. While negative regulators, also known as immunoevasins, are common, the existence of a positive regulator is without precedent and indicates an intriguing genetic potential of this virus to influence antigen presentation.
authors.affiliation: Institute for Virology, Johannes Gutenberg-University, Hochhaus am Augustusplatz, 55101 Mainz, Germany.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Holtappels
authors.forename: Dorothea
authors.initials: D
authors.lastname: Gillert-Marien
authors.forename: Doris
authors.initials: D
authors.lastname: Thomas
authors.forename: Jürgen
authors.initials: J
authors.lastname: Podlech
authors.forename: Petra
authors.initials: P
authors.lastname: Deegen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Herter
authors.forename: Silke A
authors.initials: SA
authors.lastname: Oehrlein-Karpi
authors.forename: Dennis
authors.initials: D
authors.lastname: Strand
authors.forename: Markus
authors.initials: M
authors.lastname: Wagner
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Reddehase
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics*; D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003586:Cytomegalovirus Infections / Q000276:immunology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000276:immunology / Q000821:virology; D005260:Female; D005347:Fibroblasts / Q000821:virology; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000235:genetics*; D010455:Peptides / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; D002352:Carrier Proteins; D006023:Glycoproteins; D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D010455:Peptides; D014764:Viral Proteins; C104832:gp34 protein, cytomegalovirus; C104783:m152 protein, cytomegalovirus