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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037570-08
Application #
7211472
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Utz, Ursula
Project Start
2000-02-01
Project End
2008-05-31
Budget Start
2007-04-01
Budget End
2008-05-31
Support Year
8
Fiscal Year
2007
Total Cost
$282,551
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Rayasam, Aditya; Kijak, Julie A; Dallmann, McKenna et al. (2018) Regional Distribution of CNS Antigens Differentially Determines T-Cell Mediated Neuroinflammation in a CX3CR1-Dependent Manner. J Neurosci 38:7058-7071
Clarkson, Benjamin D; Walker, Alec; Harris, Melissa G et al. (2015) CCR2-dependent dendritic cell accumulation in the central nervous system during early effector experimental autoimmune encephalomyelitis is essential for effector T cell restimulation in situ and disease progression. J Immunol 194:531-41
Harris, Melissa G; Hulseberg, Paul; Ling, Changying et al. (2014) Immune privilege of the CNS is not the consequence of limited antigen sampling. Sci Rep 4:4422
Clarkson, Benjamin D S; Ling, Changying; Shi, Yejie et al. (2014) T cell-derived interleukin (IL)-21 promotes brain injury following stroke in mice. J Exp Med 211:595-604
Clarkson, Benjamin D; Walker, Alec; Harris, Melissa et al. (2014) Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE. J Neuroimmunol 277:39-49
Clarkson, Benjamin D; Héninger, Erika; Harris, Melissa G et al. (2012) Innate-adaptive crosstalk: how dendritic cells shape immune responses in the CNS. Adv Exp Med Biol 946:309-33
Zhu, Bing; Trikudanathan, Subbulaxmi; Zozulya, Alla L et al. (2012) Immune modulation by Lacto-N-fucopentaose III in experimental autoimmune encephalomyelitis. Clin Immunol 142:351-61
Schreiber, Heidi A; Harding, Jeffrey S; Hunt, Oliver et al. (2011) Inflammatory dendritic cells migrate in and out of transplanted chronic mycobacterial granulomas in mice. J Clin Invest 121:3902-13
Schreiber, Heidi A; Hulseberg, Paul D; Lee, JangEun et al. (2010) Dendritic cells in chronic mycobacterial granulomas restrict local anti-bacterial T cell response in a murine model. PLoS One 5:e11453
Hulseberg, Paul D; Zozulya, Alla; Chu, Hamlet H et al. (2010) The same well-characterized T cell epitope SIINFEKL expressed in the context of a cytoplasmic or secreted protein in BCG induces different CD8+ T cell responses. Immunol Lett 130:36-42

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