The role of EBV latent membrane protein 1 induced regulatory T-cells in latent infection and Hodgkin lymphoma
Healthy EBV seropositive donors tested for the ability to mount Th responses against LMP1 responded with secretion of high levels of the immunosuppressive cytokine IL-10 which was secreted from cells phenotypically analogous to the Tr1 class of regulatory T-cells. The epitopes inducing this IL-10 secretion were clustered in the hydrophobic, transmembrane half of the protein that corresponded to a cluster of high affinity MHC class II binding domains. Since the LMP1 induced TO cells could effectively suppress immune responses in an IL- 10 dependent manner, it seems likely that the induction of regulatory T-cells serves to prevent anti-EBV immune responses and aid viral persistence. PBMC and HLIL from HL patients also responded to stimulation with LMP1 by predominantly secreting IL-10. However, these patients appeared to mount weaker responses compared to healthy donors. In addition, a defect in their ability to mount Th1 responses against a range of control stimuli was documented. HL patient HLIL were highly enriched for populations of both Tr1and CD4CD25 regulatory T-cells, which were strongly suppressive. Such enriched populations of regulatory T-cells may be induced by LMP1 in EBV positive cases of HL and will act to prevent anti-tumour immune responses and aid tumour growth and persistence. Thus the Th cell response to LMP1 is dominated by the induction of regulatory T-cells in both latently infected donors and HL patients. This strategy of induction of Tr cells should serve to protect EBV infected cells (either latently infected B-cells or H-RS cells) from clearance by the host. This strategy of immune evasion via the induction of Tr cells may well be found with other persistent viral infections and tumours.