Functional diversity of the CD8+ T-cell response to Epstein-Barr virus (EBV): Implications for the pathogenesis of EBV-associated lymphoproliferative disorders

Abstract

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 I 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 γ (IFNγ), but little or no interleukin-4 (IL-4), whereas the second subset was IFNγ+/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 IFNγ, 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.