T cell recruitment into the brain is an important aspect of brain inflammation in infectious and autoimmune diseases of the central nervous system (CNS). In our previous grant, we used intracerebral (IC) antigen injection and CD4+ or CD8+ T cell receptor (TCR) transgenic T cells, to study the timing and various quantitative aspects of T cell migration into the brain. Using monoclonal transgenic T cell populations allowed us to track specific and non-specific T cells. These experiments identified molecules that play a role in homing of antigen specific T cells to the brain and allowed us to formulate new hypotheses about T cell migration to the CNS. For this competitive renewal application, the first specific aim is to test our hypothesis that T cells of different specificities modify T cell homing and accumulation in the CNS. This hypothesis is supported by our preliminary data generated under our previous funding. We will use two monoclonal TCR transgenic T cell populations and inject their respective antigens IC to test how two T cells interfere with each other's homing into brain. In the second specific aim, we will test the hypothesis that this interference is mediated by altered antigen presenting cells (APC) and/or the altered local concentration of T cell growth factors. We show that local APCs, expressing dendritic cell markers, are present in the CNS upon IC antigen injection. Since antigen presentation is important for activation of T cells, in the third specific aim we will test the hypothesis that brain APCs can traffic to cervical lymph nodes (CLN) to activate T cells that are instructed to home preferentially to the brain. GFP expressing dendritic cells will be used to track their route to the lymph node and to test the role of the lymph node homing chemokine, CCR7, in this process. We will use TCR transgenic T cells and corresponding MHC tetramers and clonotypic antibodies to follow T cell movement from CLN to brain. These experiments will help us to understand the mechanisms of T cell migration and recruitment to the brain and will provide new knowledge that can contribute to T cell migration blocking therapies for brain inflammatory diseases. ? ?
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