The cell type responsible for transmission of immunologically relevant information from the central nervous system (CNS) to the peripheral immune system is currently unclear. The identification of this cell is central to understanding the genesis of innate and adaptive immune responses to CNS infection, the maladaptive immunological response to self that occurs in CNS autoimmune disease, and the escape from immunological assault that protects CNS tumors. The field has largely focused on dendritic cells and microglia as antigen presenting cells within the CNS that drive T cell restimulation, but the capacity of these cells to transmit information to the lymph nodes for original T cell priming is limited or unstudied. A long-term goal is to identify cells that carry neural antigens to the peripheral lymph nodes in order to therapeutically modify, modulate, or abrogate their function. The specific objective of this proposal is to test the ability of CD45hiCD11bhiLy6Chi Ly6Gneg inflammatory monocytes to transmit antigens from the acutely infected brain to the peripheral immune system. The central hypothesis is that inflammatory monocytes which infiltrate the brain in response to specific chemokine signals are a critical antigen-presenting cell with the capacity to exit the brain and carry antigen to the cervical lymph nodes (CLNs). The hypothesis is based upon preliminary data showing that brain-infiltrating inflammatory monocytes acquire protein antigens and virus within the brain in the first 18-24 hours after infection and carry this information to the CLNs. The main hypothesis will be tested by pursuing two specific aims: 1) To identify the mechanisms responsible for recruitment and infiltration of inflammatory monocytes into the brain during the first 48 hours of virus infection; and 2) To determine if brain-infiltratng inflammatory monocytes acquire a dendritic cell phenotype, exit the brain carrying viral antigens, and function as antigen- presenting cells in the CLNs. The experimental approach will utilize LysM:GFP reporter mice acutely infected with the Theiler's murine encephalomyelitis virus and will exploit genetic and immunological manipulation of chemokines, chemokine receptors and adhesion factors as well as adoptive transfers to test the main hypothesis. The approach is innovative because it uses a model system in which brain-restricted antigens are acquired by infiltrating inflammatory monocytes that then carry these antigens to the periphery to drive T cell responses. The proposed research is significant because it identifies an inflammatory responder that infiltrates the brain, acquires immunological information, and transmits that information to the peripheral immune system, providing an entirely new target for therapeutic and pharmacological modulation of CNS immune responses.
The proposed research is relevant to public health because identifying inflammatory monocytes as hyper-acute responders that drive peripheral immunity to CNS antigens means that strategies can be sought to enhance these cells to promote tumor clearance, suppress these cells to limit CNS autoimmunity, or modulate these cells to control CNS infection. The proposal is relevant to the mission of the NIH and NINDS because it will develop fundamental knowledge that may help to reduce the burden of disease and improve human health.
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