title: Virus-encoded ectopic CD74 enhances poxvirus vaccine efficacy.
abstract: Vaccinia virus (VV) has been used globally as a vaccine to eradicate smallpox. Widespread use of this viral vaccine has been tempered in recent years because of its immuno-evasive properties, with restrictions prohibiting VV inoculation of individuals with immune deficiencies or atopic skin diseases. VV infection is known to perturb several pathways for immune recognition including MHC class II (MHCII) and CD1d-restricted antigen presentation. MHCII and CD1d molecules associate with a conserved intracellular chaperone, CD74, also known as invariant chain. Upon VV infection, cellular CD74 levels are significantly reduced in antigen-presenting cells, consistent with the observed destabilization of MHCII molecules. In the current study, the ability of sustained CD74 expression to overcome VV-induced suppression of antigen presentation was investigated. Viral inhibition of MHCII antigen presentation could be partially ameliorated by ectopic expression of CD74 or by infection of cells with a recombinant VV encoding murine CD74 (mCD74-VV). In contrast, virus-induced disruptions in CD1d-mediated antigen presentation persisted even with sustained CD74 expression. Mice immunized with the recombinant mCD74-VV displayed greater protection during VV challenge and more robust anti-VV antibody responses. Together, these observations suggest that recombinant VV vaccines encoding CD74 may be useful tools to improve CD4⁺ T-cell responses to viral and tumour antigens.
authors.affiliation: Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Crystal C
authors.initials: CC
authors.lastname: Walline
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Deffit
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Guindon
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Crotzer
authors.forename: Jianyun
authors.initials: J
authors.lastname: Liu
authors.forename: Kristin
authors.initials: K
authors.lastname: Hollister
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Eisenlohr
authors.forename: Randy R
authors.initials: RR
authors.lastname: Brutkiewicz
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D055610:Antigens, CD1d / Q000276:immunology / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012900:Smallpox Vaccine / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology; D014615:Vaccinia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D055610:Antigens, CD1d; D000944:Antigens, Differentiation, B-Lymphocyte; D000956:Antigens, Viral; C584692:CD1d antigen, mouse; D000949:Histocompatibility Antigens Class II; D012900:Smallpox Vaccine; D014614:Vaccines, Synthetic; D014764:Viral Proteins; C045084:invariant chain
keywords: CD74; MHC; class II; invariant chain; virus