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Human Cytotoxic CD4⁺ T Cells Recognize HLA-DR1-Restricted Epitopes on Vaccinia Virus Proteins A24R and D1R Conserved among Poxviruses¹

Shibani Mitra-Kaushik^*, John Cruz^*, Lawrence J. Stern, Francis A. Ennis^* and Masanori Terajima^2,*

^* Center for Infectious Disease and Vaccine Research and Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655

We previously demonstrated that vaccinia virus (VV)-specific CD4⁺ cytolytic T cells can persist for >50 years after immunization against smallpox in the absence of re-exposure to VV. Nevertheless, there have been few studies focusing on CD4⁺ T cell responses to smallpox vaccination. To ensure successful vaccination, a candidate vaccine should contain immunodominant CD4⁺ T cell epitopes as well as CD8⁺ T and B cell epitopes. In the present study, we established cytotoxic CD4⁺ T cell lines from VV-immune donors, which recognize epitopes in VV proteins D1R and A24R in association with HLA-DR1 Ags. Comparisons of sequences between different members of the poxvirus family show that both epitopes are completely conserved among VV, variola viruses, and most mammalian poxviruses, including monkeypox, cowpox, and ectromelia. The CD4⁺ T cell lines lysed VV-infected, Ag- and peptide-pulsed targets, and the lysis was inhibited by concanamycin A. We also detected these peptide-specific cytolytic and IFN--producing CD4⁺ T cells in short-term bulk cultures of PBMC from each of the three VV-immune donors tested. These are the first VV-specific CD4⁺ T cell epitopes identified in humans restricted by one of the most common MHC class II molecules, HLA-DR1, and this information may be useful in analyzing CD4⁺ T cell responses to pre-existing or new generation VV vaccines against smallpox.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institute of Allergy and Infectious Diseases/National Institutes of Health Grants U19 AI-057319.

² Address correspondence and reprint requests to Dr. Masanori Terajima, Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. E-mail address: Masanori.Terajima{at}umassmed.edu

³ Abbreviations used in this paper: VV, vaccinia virus; BLCL, B lymphoblastoid cell line; FasL, Fas ligand; ICS, intracellular cytokine staining; moi, multiplicity of infection; MVA, modified vaccinia Ankara.

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