The central nervous system (CNS) has limited tolerance for tissue damage because of its poor regenerative capacity. Consequently, immune cells are restricted from entering, or surviving within, the healthy CNS, so that potentially auto-reactive immune response is curtailed. In spite of the immune privilege nature of the healthy CNS, immune cells can enter the infected CNS tissue. A mechanism appears to exist to limit immune response within the CNS in order to maintain tissue integrity. However the cellular and molecular components of this mechanism are not well understood. Our long-term goal is to understand these components in order to pave the way for treatment of neurological diseases. In our investigation of CNS immune response using a mouse model of neurotropic viral infection induced by encephalomyelcarditis virus (EMCV), we found that viral infection leads to CNS accumulation of effector T cells (Teffs) as well as regulatory T cells (Tregs), the latter characterized as an immune suppressive population of T cells. This supports that an immune-suppressive mechanism is initiated within the infected CNS concurrently with an antiviral immune response. Intriguingly, while Teffs appear to penetrate the infected brain parenchyma, Tregs do not enter the brain during infection. Instead, Tregs appear to localize to circumventricular organs (CVO), the gates between peripheral blood and the "moat" of cerebrospinal fluid protecting the CNS. Together this data suggests that viral infection induces CNS accumulation of Tregs, which exert suppressive function on Teffs prior to Teff infiltration of infected tissue, a novel immune-regulating mechanism employed by the CNS to minimize excessive tissue damage. This proposal aims to understand the function, localization and nature of brain Tregs during CNS viral infection. In the first aim, I will engineer EMCV to express FLAG tag and surrogate antigen, and verify that this novel virus allows tracking of infection and analysis of antigen-specific response by both effector and regulatory T cells in the infected CNS. In the second aim, I will use this new viral model, in combination with immunological and pathological methods, to determine how and where Tregs modulate Teffs. In total, the described experiments will generate new tools for the field and will elucidate the cellular mechanism by which Tregs modulate Teff entry into, and activity in, the infected brain parenchyma. As such, this proposal will reveal a novel mechanism for manipulating CNS pathology.
Diseases of the central nervous system represent a worldwide burden, impacting all age groups and segments of society. Despite the global scope of this problem, however, mechanisms regulating immune response during CNS disease are poorly understood and treatment of CNS disease is an unmet need. This research will pave the way for addressing this unmet public health need by elucidating the cellular mechanisms regulating immune response at the gates of the CNS during CNS viral infection.