Migration timeframe of germinal center-derived B cells to the central nervous system during viral encephalomyelitis.

Virus-specific humoral responses are crucial to sustain control of persisting CNS viral infections. However, the duration o-f virus specific B cell migration to the CNS relative to the sustained peripheral germinal center reactions is poorly defined. AID-CreERT2:Rosa26loxP-tdTomato reporter mice were used to track CNS migration and infiltration of virus-activated B cells during neurotropic murine coronavirus induced encephalomyelitis and persistence. Staggered tamoxifen treatment (14-21, 21-28, and 28-35 days post infection) to induce irreversible labeling of B cells undergoing somatic hypermutation, revealed that newly labelled tdTomato+ B cells primarily migrated to the CNS during early germinal center responses in the draining cervical lymph nodes. Although B cell labeling in germinal centers continued at later times, their migration to the CNS rapidly waned. All tdTomato+ cells migrated to demyelinated lesions, where they distributed to both parenchymal and perivascular spaces. However, tdTomato+ CD138- B cells preferentially localized to the parenchyma and CD138+ antibody secreting cells (ASC) to perivascular sites at early time points suggesting distinct homing cues. Prolonged survival of ASC within the CNS was supported by sustained levels as well as avidity of virus-specific antibodies. Overall, our data indicate that tdTomato+ B cell migration to the persistently infected CNS is limited to a narrow window during early germinal center responses correlating with elevated levels of CNS viral RNA rather than ongoing demyelination. Despite declining viral RNA and discontinued B cell recruitment to the CNS, resident ASC sustained local virus-specific antibody levels during virus persistence.