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Using the TAP Component of the Antigen-Processing Machinery as a Molecular Adjuvant
Vitalis, Timothy Z. Zhang, Qian-Jin Alimonti, Judie Chen, Susan S. Basha, Genc Moise, Alexander R. Tiong, Jacqueline Tian, Mei Mei Bok Choi, Kyung Waterfield, Douglas
Vitalis, Timothy Z.
Zhang, Qian-Jin
Alimonti, Judie
Chen, Susan S.
Basha, Genc
Moise, Alexander R.
Tiong, Jacqueline
Tian, Mei Mei
Bok Choi, Kyung
Waterfield, Douglas
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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.
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This is the publisher's version, also available electronically from "journals.plos.org".
Date
2005-12-30
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Public Library of Science
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Vitalis 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.0010036