"Epstein Barr virus infection and immune evasion strategies in the multiple sclerosis brain: focus on the PD-1/PD-L1 axis

Epstein-Barr virus (EBV) infection shows the stronger causative association with MS [1] but its role in MS progression, and the mechanisms underlying viral persistence in MS brain are still under investigation. Studies in postmortem brain tissue from donors with progressive MS, revealed the presence of both EBV-infected B-cells and EBV-specific cytotoxic T-cells in the CNS inflammatory infiltrates, signs of a persistent intracerebral EBV infection in advanced stages of the disease. A continuous antiviral cytotoxic response may cause tissue damage but failing to eradicate the infection, possibly due to virus-induced immune evasion mechanisms. One of these could consist in the induction of the inhibitory immune checkpoint “protein programmed cell death ligand-1” (PD-L1) in the infected B-cells that, engaging its receptor PD-1 on the T cell surface, inhibits T cell activation and the related cytotoxic function. It is known that PD-L1 is inducible in EBV+ tumors by latent EBV proteins, particularly EBNA2 and LMPs, with IFNγ acting in a synergistic manner. EBV likely evades immunity by inducing PD-L1 upon reactivation through the increased expression of EBNA2 and activation of signaling pathways Moreover, the PD-1/PD-L1 interaction plays a physiological role in germinal center formation and reaction: PD-L1, expressed on follicular dendritic cells (FDCs) and stromal cells, interacts with PD-1 on follicular helper T cells, influencing B cell survival and clonal expansion. In order to achieve these aims, we have analyzed post-mortem brain tissue from patients with progressive MS using a combination of immunohistochemical, double immunofluorescence, in situ pentamer binding and in situ hybridization techniques.