Primary CD4+ T-cell responses provide both helper and cytotoxic functions during EBV infection and transformation of foetal cord blood B-cells

Most humans carry Epstein Barr Virus (EBV) in circulating memory B-cells as a latent infection that is controlled by an immune response. When infected by EBV, B-lymphocytes in fetal cord blood are readily transformed to lymphoblastoid cell lines (LCL). It is frequently assumed that this high efficiency of transformation is due to the absence of a primary immune response. However, cord blood lymphocytes stimulated with autologous LCL yield CD4+ T-cells that can completely inhibit the growth of LCL by an MHC-restricted cytotoxic mechanism mediated through granulysin and granzyme-B. Because EBV-transformed B-cells maintain the phenotype of antigen activated B-cell blasts, they can potentially receive inhibitory or helper functions from CD4+ T-cells. To assess these functions, the effect of EBV specific CD4+ T-cells on the efficiency of virus transformation of autologous B-cells was assayed. Paradoxically, although the cytotoxic CD4+ T-cell lines reduced EBV B-cell transformation at a high effector/target ratio of 10:1 they caused a two-fold increase in B-cell transformation at the lower effector/target ratio of 1:1. Th1 polarized CD4+ T-cells were more effective at inhibiting B-cell transformation, but Th2-polarized cell lines had reduced cytotoxic activity, were unable to inhibit LCL growth and caused a 10-fold increase in transformation efficiency. Tonsil lymphoid follicles lacked NK cells and CD8+T-cells but contained CD4+ T-cells. We propose that CD4+ T-cells provide helper or cytotoxic functions to EBV-transformed B-cells and the balance of these functions within tonsil compartments is critical in establishing asymptomatic primary EBV infection and maintaining a stable lifelong latent infection.