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Functional Diversity of the CD8+ T-Cell Response to
Epstein-Barr Virus (EBV): Implications for the Pathogenesis of
EBV-Associated Lymphoproliferative Disorders
Rachel A. Nazaruk,
Rosemary Rochford,
Monte V. Hobbs, and
Martin J. Cannon
From the Department of Microbiology and Immunology, University of
Arkansas for Medical Sciences, Little Rock, AR; and the Department of
Epidemiology, University of Michigan, Ann Arbor, MI.
Epstein-Barr virus (EBV)-specific CD8+ cytotoxic T
cells are thought to be critical for the control of EBV, which persists in healthy individuals as a latent infection of B cells. However, recent observations have indicated that CD8+ T-cell
responses are not uniformly cytotoxic and that CD8+ T
cells may be subdivided into type 1 and type 2 subsets that parallel
the classically described Th1 and Th2 subsets of CD4+ T
cells. Using two-color flow cytometric analysis of intracellular cytokine expression at the single-cell level, we have identified two
distinct but overlapping subsets of EBV-specific CD8+ T
cells, the first of which expressed high levels of interferon  (IFN), but little or no interleukin-4 (IL-4), whereas the second subset was IFN+/IL-4+ double-positive. A
significant proportion of EBV-specific CD8+ T cells also
expressed IL-13. Subsequent analysis of a panel of 27 EBV-specific
CD8+ T-cell clones showed inverse relationships between
EBV-specific cytotoxicity and secretion of IL-4, IL-10, and IFN,
respectively. IL-10 was not secreted by the 11 most strongly cytotoxic
clones, suggesting that IL-10 secretion may provide a functional
definition of an EBV-specific type 2 CD8+ T-cell subset
with reduced EBV-specific cytotoxicity. Finally, we have demonstrated
that EBV-specific CD8+ T cells that express type 2 cytokines possess the ability to activate resting B cells. EBV-specific
CD8+ T cells thus have the potential to reactivate latent
EBV infection in vivo and may contribute to the development of
EBV-associated lymphoproliferative disorders and lymphoma.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3875-3883
© 1998 by The American Society of Hematology.
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