Poor Antigen Processing of Poxvirus Particles Limits CD4 + T Cell Recognition and Impacts Immunogenicity of the Inactivated Vaccine.
| Autor: | Forsyth KS; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., DeHaven B; Department of Biology, La Salle University, Philadelphia, PA 19141., Mendonca M; Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107., Paul S; La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037., Sette A; La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.; Department of Medicine, University of California, San Diego, La Jolla, CA, 92093; and., Eisenlohr LC; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; eisenlc@pennmedicine.upenn.edu.; Children's Hospital of Philadelphia, Philadelphia, PA 19104. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2019 Mar 01; Vol. 202 (5), pp. 1340-1349. Date of Electronic Publication: 2019 Jan 30. |
| DOI: | 10.4049/jimmunol.1801099 |
| Abstrakt: | CD4 + T cells play critical roles in defending against poxviruses, both by potentiating cellular and humoral responses and by directly killing infected cells. Despite this central role, the basis for pox-specific CD4 + T cell activation, specifically the origin of the poxvirus-derived peptides (epitopes) that activate CD4 + T cells, remains poorly understood. In addition, because the current licensed poxvirus vaccines can cause serious adverse events and even death, elucidating the requirements for MHC class II (MHC-II) processing and presentation of poxviral Ags could be of great use. To address these questions, we explored the CD4 + T cell immunogenicity of ectromelia, the causative agent of mousepox. Having identified a large panel of novel epitopes via a screen of algorithm-selected synthetic peptides, we observed that immunization of mice with inactivated poxvirus primes a virtually undetectable CD4 + T cell response, even when adjuvanted, and is unable to provide protection against disease after a secondary challenge. We postulated that an important contributor to this outcome is the poor processability of whole virions for MHC-II-restricted presentation. In line with this hypothesis, we observed that whole poxvirions are very inefficiently converted into MHC-II-binding peptides by the APC as compared with subviral material. Thus, stability of the virion structure is a critical consideration in the rational design of a safe alternative to the existing live smallpox vaccine. (Copyright © 2019 by The American Association of Immunologists, Inc.) |
| Databáze: | MEDLINE |
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