The Journal of Experimental Medicine
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Published 6 September 2005. doi:10.1084/jem.20050882
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 5, 673-685
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ARTICLE

 Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects

Andrew W. Sylwester1, Bridget L. Mitchell1, John B. Edgar1, Cara Taormina1, Christian Pelte1, Franziska Ruchti1, Paul R. Sleath2, Kenneth H. Grabstein2, Nancy A. Hosken2, Florian Kern3, Jay A. Nelson1, and Louis J. Picker1

1 Vaccine and Gene Therapy Institute, Departments of Pathology and Molecular Microbiology and Immunology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
2 Corixa Corporation, Seattle, WA 98104
3 Institut für Medizinische Immunologie, Charité, 10098 Berlin, Germany

CORRESPONDENCE Louis J. Picker: pickerl{at}ohsu.edu

Human cytomegalovirus (HCMV) infections of immunocompetent hosts are characterized by a dynamic, life-long interaction in which host immune responses, particularly of T cells, restrain viral replication and prevent disease but do not eliminate the virus or preclude transmission. Because HCMV is among the largest and most complex of known viruses, the T cell resources committed to maintaining this balance have never been characterized completely. Here, using cytokine flow cytometry and 13,687 overlapping 15mer peptides comprising 213 HCMV open reading frames (ORFs), we found that 151 HCMV ORFs were immunogenic for CD4+ and/or CD8+ T cells, and that ORF immunogenicity was influenced only modestly by ORF expression kinetics and function. We further documented that total HCMV-specific T cell responses in seropositive subjects were enormous, comprising on average ~10% of both the CD4+ and CD8+ memory compartments in blood, whereas cross-reactive recognition of HCMV proteins in seronegative individuals was limited to CD8+ T cells and was rare. These data provide the first glimpse of the total human T cell response to a complex infectious agent and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.

Abbreviations used: CFC, cytokine flow cytometry; dPBS, Dulbecco's PBS; HCMV, human cytomegalovirus; IE, immediate-early; ORF, open reading frame.


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