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Journal of Virology, September 2007, p. 10081-10091, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00330-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Differential Functional Avidity of Dengue Virus-Specific T-Cell Clones for Variant Peptides Representing Heterologous and Previously Encountered Serotypes{triangledown}

Allison Imrie,1* Janet Meeks,2 Alexandra Gurary,2 Munkhzul Sukhbataar,1 Paul Kitsutani,3 Paul Effler,3 and Zhengshan Zhao1,2,{dagger}

Department of Public Health Sciences,1 Department of Pediatrics, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii,2 Disease Outbreak Control Division, Hawaii State Department of Health, Honolulu, Hawaii3

Received 14 February 2007/ Accepted 20 June 2007

Proinflammatory cytokines secreted by memory CD8+ and CD4+ T cells are thought to play a direct role in the pathogenesis of dengue virus infection by increasing vascular permeability and thereby inducing the pathophysiologic events associated with dengue hemorrhagic fever and dengue shock syndrome. Severe disease is frequently observed in the setting of secondary infection with heterologous dengue virus serotypes, suggesting a role for cross-reactive memory T cells in the immunopathogenesis of severe disease. We used a large panel of well-characterized dengue virus-specific CD8+ T-cell clones isolated from Pacific Islanders previously infected with dengue virus 1 to examine effector memory function, focusing on a novel dominant HLA-B*5502-restricted NS5329-337 epitope, and assessed T-cell responses to stimulation with variant peptides representing heterologous serotypes. Variant peptides were differentially recognized by dengue virus 1-specific effector CD8+ cytotoxic T lymphocytes (CTL) in a heterogeneous and clone-specific manner, in which cytolytic function and cytokine secretion could be enhanced, diminished, or abrogated compared with cognate peptide stimulation. Dengue virus-specific CTL stimulated with cognate and variant peptides demonstrated a cytokine response hierarchy of gamma IFN (IFN-{gamma}) > tumor necrosis factor alpha (TNF-{alpha}) > interleukin-2 (IL-2), and a subset of clones also produced IL-4 and IL-6. Individual clones demonstrated greater avidity for variant peptides representing heterologous serotypes, including serotypes previously encountered by the subject, and IFN-{gamma} and TNF-{alpha} secretion was enhanced by stimulation with these heterologous peptides. Altered antiviral T-cell responses in response to stimulation with heterologous dengue virus serotypes have implications for control of virus replication and for disease pathogenesis.

* Corresponding author. Mailing address: John A. Burns School of Medicine, Department of Public Health Sciences, Biosciences Building, Room 325E, 651 Ilalo Street, Honolulu, HI 96813. Phone: (808) 692-1667. Fax: (808) 692-1984. E-mail: imrie{at}pbrc.hawaii.edu

{triangledown} Published ahead of print on 11 July 2007.

{dagger} Present address: R-709, Infectious Disease Research Center, CHUL, Université Laval, 2705 Blvd. Laurier, Quebec, Canada G1V 4G2.

Journal of Virology, September 2007, p. 10081-10091, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00330-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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