title: Regression of Epstein-Barr virus-induced B-cell transformation in vitro involves virus-specific CD8+ T cells as the principal effectors and a novel CD4+ T-cell reactivity.
abstract: T-cell memory to Epstein-Barr virus (EBV) was first demonstrated through regression of EBV-induced B-cell transformation to lymphoblastoid cell lines (LCLs) in virus-infected peripheral blood mononuclear cell (PBMC) cultures. Here, using donors with virus-specific T-cell memory to well-defined CD4 and CD8 epitopes, we reexamine recent reports that the effector cells mediating regression are EBV latent antigen-specific CD4+ and not, as previously assumed, CD8+ T cells. In regressing cultures, we find that the reversal of CD23+ B-cell proliferation was always coincident with an expansion of latent epitope-specific CD8+, but not CD4+, T cells; furthermore CD8+ T-cell clones derived from regressing cultures were epitope specific and reproduced regression when cocultivated with EBV-infected autologous B cells. In cultures of CD4-depleted PBMCs, there was less efficient expansion of these epitope-specific CD8+ T cells and correspondingly weaker regression. The data are consistent with an effector role for epitope-specific CD8+ T cells in regression and an auxiliary role for CD4+ T cells in expanding the CD8 response. However, we also occasionally observed late regression in CD8-depleted PBMC cultures, though again without any detectable expansion of preexisting epitope-specific CD4+ T-cell memory. CD4+ T-cell clones derived from such cultures were LCL specific in gamma interferon release assays but did not recognize any known EBV latent cycle protein or derived peptide. A subset of these clones was also cytolytic and could block LCL outgrowth. These novel effectors, whose antigen specificity remains to be determined, may also play a role in limiting virus-induced B-cell proliferation in vitro and in vivo.
authors.affiliation: CRUK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Gudgeon
authors.forename: Graham S
authors.initials: GS
authors.lastname: Taylor
authors.forename: Heather M
authors.initials: HM
authors.lastname: Long
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Haigh
authors.forename: Alan B
authors.initials: AB
authors.lastname: Rickinson
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte; D004854:Herpesvirus 4, Human; D006801:Humans; D007156:Immunologic Memory; D007963:Leukocytes, Mononuclear; D017455:Receptors, IgE
chemical_list: D018984:Epitopes, T-Lymphocyte; D017455:Receptors, IgE