title: Using the TAP component of the antigen-processing machinery as a molecular adjuvant.
abstract: We hypothesize that over-expression of transporters associated with antigen processing (TAP1 and TAP2), components of the major histocompatibility complex (MHC) class I antigen-processing pathway, enhances antigen-specific cytotoxic activity in response to viral infection. An expression system using recombinant vaccinia virus (VV) was used to over-express human TAP1 and TAP2 (VV-hTAP1,2) in normal mice. Mice coinfected with either vesicular stomatitis virus plus VV-hTAP1,2 or Sendai virus plus VV-hTAP1,2 increased cytotoxic lymphocyte (CTL) activity by at least 4-fold when compared to coinfections with a control vector, VV encoding the plasmid PJS-5. Coinfections with VV-hTAP1,2 increased virus-specific CTL precursors compared to control infections without VV-hTAP1,2. In an animal model of lethal viral challenge after vaccination, VV-hTAP1,2 provided protection against a lethal challenge of VV at doses 100-fold lower than control vector alone. Mechanistically, the total MHC class I antigen surface expression and the cross-presentation mechanism in spleen-derived dendritic cells was augmented by over-expression of TAP. Furthermore, VV-hTAP1,2 increases splenic TAP transport activity and endogenous antigen processing, thus rendering infected targets more susceptible to CTL recognition and subsequent killing. This is the first demonstration that over-expression of a component of the antigen-processing machinery increases endogenous antigen presentation and dendritic cell cross-presentation of exogenous antigens and may provide a novel and general approach for increasing immune responses against pathogens at low doses of vaccine inocula.
authors.affiliation: The Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Timothy Z
authors.initials: TZ
authors.lastname: Vitalis
authors.forename: Qian-Jin
authors.initials: QJ
authors.lastname: Zhang
authors.forename: Judie
authors.initials: J
authors.lastname: Alimonti
authors.forename: Susan S
authors.initials: SS
authors.lastname: Chen
authors.forename: Genc
authors.initials: G
authors.lastname: Basha
authors.forename: Alex
authors.initials: A
authors.lastname: Moise
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Tiong
authors.forename: Mei Mei
authors.initials: MM
authors.lastname: Tian
authors.forename: Kyung Bok
authors.initials: KB
authors.lastname: Choi
authors.forename: Douglas
authors.initials: D
authors.lastname: Waterfield
authors.forename: Andy
authors.initials: A
authors.lastname: Jeffries
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: Jefferies