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,
,¶,#,**
* Department of Medicine,
Department of Laboratory Medicine, University of Washington, Seattle, WA 98101;
School of Veterinary Medicine,
School of Dental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
¶ Benaroya Research Institute, Seattle, WA 98101;
|| La Jolla Institute for Allergy and Immunology, San Diego, CA 92121;
# Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
** Program in Pathobiology, University of Washington, Seattle, WA 98101
Vaccination with replication-competent vaccinia protects against heterologous orthopoxvirus challenge. CD4 T cells have essential roles helping functionally important Ab and CD8 antiviral responses, and contribute to the durability of vaccinia-specific memory. Little is known about the specificity, diversity, or dominance hierarchy of orthopoxvirus-specific CD4 T cell responses. We interrogated vaccinia-reactive CD4 in vitro T cell lines with vaccinia protein fragments expressed from an unbiased genomic library, and also with a panel of membrane proteins. CD4 T cells from three primary vaccinees reacted with 44 separate antigenic regions in 35 vaccinia proteins, recognizing 8 to 20 proteins per person. The integrated responses to the Ags that we defined accounted for 49 to 81% of the CD4 reactivity to whole vaccinia Ag. Individual dominant Ags drove up to 30% of the total response. The gene F11L-encoded protein was immunodominant in two of three subjects and is fragmented in a replication-incompetent vaccine candidate. The presence of protein in virions was strongly associated with CD4 antigenicity. These findings are consistent with models in which exogenous Ag drives CD4 immunodominance, and provides tools to investigate the relationship between Ab and CD4 T cell specificity for complex pathogens.
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 National Institutes of Health Grants AI061636 and AI067496 (to D.M.K.), AI062486 and AI057168 (to G.H.C. and R.J.E.), and AI56268 and HHSN266200400124C (to A.S.).
2 Address correspondence and reprint requests to Dr. David Koelle, 1616 Eastlake Avenue E., Suite 500, Box 358117, Seattle, WA 98102. E-mail addresss: viralimm{at}u.washington.edu
3 Abbreviations used in this paper: MVA, modified vaccinia Ankara; ICC, intracellular cytokine cytometry; WR, Western Reserve; TCM, T cell medium; ORF, open reading frame.
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