Regulatory T cell activity in primary and persistent Epstein-Barr virus infection

Regulatory T cells (T(reg)) provide a balance to immune T cell activation thereby protecting the body from pathogen-induced immunopathology. Several persistent viruses induce T(reg) that subvert protective immune mechanisms and promote viral persistence. Epstein-Barr virus (EBV) generally infects children subclinically and persists thereafter, but primary infection in early adulthood may cause immunopathological damage manifest as infectious mononucleosis. In this study the role of T(reg) was investigated in acute infectious mononucleosis and healthy EBV seropositive donors. The proportion of CD4(+)CD25(high) T cells in blood from infectious mononucleosis patients was significantly lower than in seropositive donors (P = 0.05). Using the FOXP3 marker for T(reg) the same frequency and extra-follicular distribution of T(reg) was noted in infectious mononucleosis and control tonsils. Regulatory cytokines, interleukin (IL)-10 and transforming growth factor (TGF)-beta, were significantly raised in infectious mononucleosis compared to seropositive donor plasma (P = 0.0001, P = 0.0004 respectively) although levels of IL-10 peaked earlier in infectious mononucleosis than TGF-beta. Previous studies identified EBV latent membrane protein (LMP)-1-induced T(reg) activity [Marshall et al. (2003): J Immunol 170:6183-6189; Marshall et al. (2007): Brit J Haematol 139:81-89], and in this study a significant reduction in interferon-gamma production was found from infectious mononucleosis but not seropositive donor lymphocytes after stimulation with a recall antigen when LMP-1 peptide PRG was added (P = 0.03). It is possible that T(reg) are important in controlling primary EBV infection to a subclinical level in most cases and that infectious mononucleosis represents a failure of this protective mechanism.