Functional diversity of the CD8(+) T-cell response to Epstein-Barr virus (EBV): implications for the pathogenesis of EBV-associated lymphoproliferative disorders.
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 gamma (IFNgamma), but little or no interleukin-4 (IL-4), whereas the second subset was IFNgamma+/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 IFNgamma, 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.
Nazaruk
R A
RA
Department of Microbiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Rochford
R
R
Hobbs
M V
MV
Cannon
M J
MJ
D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000378:metabolism / Q000821:virology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D006566:Herpesviridae Infections / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D008222:Lymphokines / Q000378:metabolism*; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000821:virology*; D018448:Models, Immunological; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000821:virology*; D014412:Tumor Virus Infections / Q000276:immunology*
D018793:Interleukin-13; D008222:Lymphokines; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma