The Role Of CD95 Signaling In EBV-associated Lymphoproliferative Diseases

Epstein-Barr virus(EBV)is a ubiquitous gammaherpesvirus,infecting more than 90% of the population all over the world,which greatly increases the risk of lymphoproliferative disorders and lymphomas.CD95,also known as Fas and apoptosis antigen 1,belongs to tumor necrosis factor receptor superfamily.It has been demonstrated that the non-apoptotic signaling of CD95 plays an important role in cancers,and our previous study has also shown that CD95 ligand(CD95L)-mediated CD95 signaling inhibits EBV reactivation through inducing IFN-β.Here,we extended our study to further define whether membrane-bound CD95L(m-CD95L)or soluble cleavage form of CD95 L are responsible for the inhibition of EBV reactivation.Our data shows that high concentration of m-CD95 L stimulation induces apoptosis of EBVimmortalized lymphoblastoid cells(LCLs),whereas lower concentration of m CD95 L stimulation suppresses EBV lytic gene expression without affecting the promoter activity of EBV immediate-early genes Zta and RTA.Stimulation of m CD95 L inhibits B cell receptor signaling pathway through downregulation of surface CD19 expression and correspondingly inhibits EBV lytic gene expression,which can be blocked by CD95 neutralizing antibody,indicating that CD95-mediating signaling regulates EBV lytic gene expression by interfering BCR signaling pathway.Our finding illustrates an important role of m-CD95L-mediated CD95 signaling in EBV-associated LCLs which recapitulate EBV-associated post-transplant lymphoproliferative diseases,raising a critical issue in T cell immunotherapy.