Vitalis, Timothy Z.Zhang, Qian-JinAlimonti, JudieChen, Susan S.Basha, GencMoise, Alexander R.Tiong, JacquelineTian, Mei MeiBok Choi, KyungWaterfield, DouglasJeffries, AndyJefferies, Wilfred A.2015-05-112015-05-112005-12-30Vitalis TZ, Zhang Q-J, Alimonti J, Chen SS, Basha G, Moise A, et al. (2005) Using the TAP Component of the Antigen-Processing Machinery as a Molecular Adjuvant. PLoS Pathog 1(4): e36. http://www.dx.doi.org/10.1371/journal.ppat.0010036https://hdl.handle.net/1808/17685This is the publisher's version, also available electronically from "journals.plos.org".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.Article10.1371/journal.ppat.0010036https://orcid.org/0000-0003-2307-6035openAccess