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Little is known about CD4+ T cell entry into the central nervous system (CNS) in the absence of inflammation. Attenuated rabies viruses (RABV) are unique tools to study this process, as they spread from the site of inoculation to the CNS trans-axonally, without compromising the blood-brain barrier. Previous studies with live-attenuated RABV showed that CD4+ T cell entry into the CNS is associated with an increase in IFN-g mRNA in the brain and the production of IgG2a antibodies in the periphery, indicating a bias towards TH1 immunity. To further investigate the nature of the CD4+ T cells involved in the CNS response to RABV, we performed a temporal comparison of development of antiviral immunity in C57BL/6 and T-Bet knock-out (T-Bet-/-) mice. In both mouse strains, we observed that virus spread through the CNS is associated with elevated IFN-g mRNA, but that immune cell infiltration and antibody production in CNS tissues differs significantly. Immune cell infiltration into the CNS is significantly lower in T-Bet-/- mice at day 8 post-infection. Moreover, despite the fact that immunized T-Bet-/- mice produce a substantial amount of neutralizing antibody in the periphery and are fully protected against i.m. challenge with pathogenic RABV, they are unable to survive an i.c. challenge with the same virus. Together, these findings suggest that TH1 cells play a critical role in cell infiltration into the CNS and the clearance of RABV despite the absence of inflammatory pathology.

Funding: Supported by grants from NIH (RO1 AI093369-01)