EBV induces CNS homing of B cells attracting inflammatory T cells

Epidemiological data have identified Epstein-Barr virus (EBV) infection as the main environmental risk factor for the central nervous system (CNS) autoimmune disease multiple sclerosis (MS). However, how EBV infection initiates MS pathogenesis remains unclear. We now demonstrate that EBV differentiates oligoclonal B cells into MS-associated T-bet+CXCR3+ B cells that home to the CNS in humanized mice. Effector memory CD8+ T cells and CD4+ TH17 cells co-migrate to the brain of EBV infected humanized mice. T-bet+CXCR3+ B cells are capable of colonizing submeningeal brain regions in the absence of other lymphocytes and attract T cells. Depletion of this T-bet+CXCR3+ B cell subset with Rituximab significantly decreases lymphocyte infiltration into the CNS. Thus, we suggest that symptomatic primary EBV infection generates B cell subsets that gain access to the CNS, attract T cells and thereby initiate MS. Humanised BRGS-A2DR2 mice were infected with EBV and monitored for 6 weeks. After 6 weeks, spleens (n=3) were dissociated and CD19+ B cells were fluorescence-activated cell sorted (FACS). Joint scRNAseq and scBCRseq libraries were prepared from CD19+ B cells using the 10x Genomics platform.