Langerhans cells are a type of dendritic cell uniquely positioned to play a vital role in immunity at the barrier surfaces. They form a network at the base of stratified epithelium in the skin. They have potent antigen presenting function in vitro, and promote robust immune responses in vivo, as we showed in the previous funding period. However, they are also thought to play a role in tolerance and immunological suppression, particularly after low dose UVB irradiation. There is also growing interest in the role of Langerhans cells in epicutaneous immunization, a strategy that shows surprising efficacy against viral and bacterial infection, and tumors. Nonetheless/many basic properties of Langerhans cells are uncharacterized at present: including whether they can cross-present MHCClass I antigens, if they can induce peripheral tolerance, and how their immunological properties are changed after insult or injury to the skin. Fortunately, the field is rapidly developing incisive tools to study this population. In the current application we propose to utilize someof these new tools and develop others, that together will allow us to answer specific questions about the role of Langerhans cells (LC) in peripheral tolerance to epidermal antigens. We propose to create and study TCR transgenics with high and low affinity for a naturally occurring epidermal antigen: tryosinase related protein 2 (trp2). We will define the ARC responsible for processing and presentation of trp2180-188, using bone marrow chimeras and inducibly LC deficient mice. We will also study the role of Langerhans cells in tolerance and immunity to exogenousantigens introduced through the skin (epicutaneous immunization or ECI) by developing an ovalbumin-based model system. Using this we will be able to test specific hypotheses about how skin immune response modifiers, Imiquimod, CPG DNA, and UVB irradiation, influence immunity and tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI035296-17
Application #
7895076
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
17
Fiscal Year
2009
Total Cost
$332,881
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Burrack, Adam L; Malhotra, Deepali; Dileepan, Thamotharampillai et al. (2018) Cutting Edge: Allograft Rejection Is Associated with Weak T Cell Responses to Many Different Graft Leukocyte-Derived Peptides. J Immunol 200:477-482
Breed, Elise R; Lee, S Thera; Hogquist, Kristin A (2018) Directing T cell fate: How thymic antigen presenting cells coordinate thymocyte selection. Semin Cell Dev Biol 84:2-10
Osum, Kevin C; Burrack, Adam L; Martinov, Tijana et al. (2018) Interferon-gamma drives programmed death-ligand 1 expression on islet ? cells to limit T cell function during autoimmune diabetes. Sci Rep 8:8295
Ruscher, Roland; Hogquist, Kristin A (2018) Intravenous Labeling and Analysis of the Content of Thymic Perivascular Spaces. Bio Protoc 8:
Kotov, Dmitri I; Kotov, Jessica A; Goldberg, Michael F et al. (2018) Many Th Cell Subsets Have Fas Ligand-Dependent Cytotoxic Potential. J Immunol 200:2004-2012
Leonard, John D; Gilmore, Dana C; Dileepan, Thamotharampillai et al. (2017) Identification of Natural Regulatory T Cell Epitopes Reveals Convergence on a Dominant Autoantigen. Immunity 47:107-117.e8
Schuldt, Nathaniel J; Auger, Jennifer L; Spanier, Justin A et al. (2017) Cutting Edge: Dual TCR? Expression Poses an Autoimmune Hazard by Limiting Regulatory T Cell Generation. J Immunol 199:33-38
Kalekar, Lokesh A; Mueller, Daniel L (2017) Relationship between CD4 Regulatory T Cells and Anergy In Vivo. J Immunol 198:2527-2533
Burrack, Adam L; Martinov, Tijana; Fife, Brian T (2017) T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes. Front Endocrinol (Lausanne) 8:343
Ruscher, Roland; Kummer, Rebecca L; Lee, You Jeong et al. (2017) CD8?? intraepithelial lymphocytes arise from two main thymic precursors. Nat Immunol 18:771-779

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