title: T-cell reprogramming through targeted CD4-coreceptor and T-cell receptor expression on maturing thymocytes by latent Circoviridae family member porcine circovirus type 2 cell infections in the thymus.
abstract: Although porcine circovirus type 2 (PCV2)-associated diseases have been evaluated for known immune evasion strategies, the pathogenicity of these viruses remained concealed for decades. Surprisingly, the same viruses that cause panzootics in livestock are widespread in young, unaffected animals. Recently, evidence has emerged that circovirus-like viruses are also linked to complex diseases in humans, including children. We detected PCV2 genome-carrying cells in fetal pig thymi. To elucidate virus pathogenicity, we developed a new pig infection model by in vivo transfection of recombinant PCV2 and the immunosuppressant cofactor cyclosporine A. Using flow cytometry, immunofluorescence and fluorescence in situ hybridization, we found evidence that PCV2 dictates positive and negative selection of maturing T cells in the thymus. We show for the first time that PCV2-infected cells reside at the corticomedullary junction of the thymus. In diseased animals, we found polyclonal deletion of single positive cells (SPs) that may result from a loss of major histocompatibility complex class-II expression at the corticomedullary junction. The percentage of PCV2 antigen-presenting cells correlated with the degree of viremia and, in turn, the severity of the defect in thymocyte maturation. Moreover, the reversed T-cell receptor/CD4-coreceptor expression dichotomy on thymocytes at the CD4(+)CD8(interm) and CD4SP cell stage is viremia-dependent, resulting in a specific hypo-responsiveness of T-helper cells. We compare our results with the only other better-studied member of Circoviridae, chicken anemia virus. Our data show that PCV2 infection leads to thymocyte selection dysregulation, adding a valuable dimension to our understanding of virus pathogenicity.
authors.affiliation: Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich , CH-8057 Zurich, Switzerland ; Department of Farm Animals, Division of Swine Medicine, Vetsuisse Faculty, University of Zurich , CH-8057-Zurich, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Klausmann
authors.affiliation: Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich , CH-8057 Zurich, Switzerland.
authors.forename: Titus
authors.initials: T
authors.lastname: Sydler
authors.affiliation: Institute of Virology and Immunology (IVI) , 3147 Mittelhäusern, Switzerland.
authors.forename: Artur
authors.initials: A
authors.lastname: Summerfield
authors.affiliation: Section of Epidemiology, Vetsuisse Faculty, University of Zurich , CH-8057 Zurich, Switzerland.
authors.forename: Fraser I
authors.initials: FI
authors.lastname: Lewis
authors.affiliation: Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich , CH-8057 Zurich, Switzerland.
authors.forename: Roseline
authors.initials: R
authors.lastname: Weilenmann
authors.affiliation: Department of Farm Animals, Division of Swine Medicine, Vetsuisse Faculty, University of Zurich , CH-8057-Zurich, Switzerland.
authors.forename: Xaver
authors.initials: X
authors.lastname: Sidler
authors.affiliation: Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich , CH-8057 Zurich, Switzerland ; Department of Farm Animals, Division of Swine Medicine, Vetsuisse Faculty, University of Zurich , CH-8057-Zurich, Switzerland.
authors.forename: Enrico
authors.initials: E
authors.lastname: Brugnera
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D018173:Circoviridae Infections / Q000276:immunology / Q000662:veterinary* / Q000821:virology; D017925:Circovirus / Q000276:immunology* / Q000472:pathogenicity; D016572:Cyclosporine / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006041:Goats; D057131:Immune Evasion; D007166:Immunosuppressive Agents / Q000276:immunology; D008297:Male; D051379:Mice; D011897:Random Allocation; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D013552:Swine; D013553:Swine Diseases / Q000276:immunology / Q000821:virology*; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000821:virology*; D014162:Transfection
chemical_list: D015704:CD4 Antigens; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D016572:Cyclosporine
keywords: CD4+ thymocyte maturation diversion; Circoviridae porcine circovirus type 2 pathogenicity; T-helper cell hypo-responsiveness; adaptive immune response failure; dendritic cell feedback; in vivo anergy; polyclonal negative selection; thymic kinetic signaling model