Skin dendritic cells (DC) are efficient antigen-presenting cells that are a critical component of the cutaneous immune system. The best characterized skin DC subset is the Langerhans cell (LC) that resides in the epidermis of the skin and is the first DC population to encounter cutaneous pathogens, environmental insults and epidermal neoplasia. Major obstacles to studying the function of skin DC include: the difficulty in accurately identifying skin DC subsets;the inability to test the functional importance of DC subsets in vivo;and the absence of a physiologic model system in which antigen-specific responses to cutaneous antigens can be examined in vivo. We believe that we have overcome some of these obstacles though the development transgenic mice that have a specific, complete and durable absence of LC. Using classic assays of the cutaneous immune response we have shown that contact hypersensitivity (CHS) and rejection of allogeneic skin grafts do not require LC. Instead, we found that CHS responses and rejection of minor-mismatched skin grafts were enhanced in the absence of LC. Moreover, we have also recently discovered markers that identify a novel DC subset in the dermis that is required for efficient CHS responses. We propose to exploit these tools to examine the mechanism of LC-mediated regulation of CHS. We will examine whether LC-mediated regulation occurs during the steady-state or at the time of immunization and whether LC-derived IL-10 or TGF2 are required. We will also compare the expression profile of LC with other skin DC subsets by microarray. Finally, we will generate an antigen-specific infection model by combining an existing model of cutaneous Candidiasis with Candida albicans that we will engineer to express ovalbumin. We will be able to use this model to examine whether LC regulate or promote immune responses to yeast and how LC affect the development of antigen-specific responses.

Public Health Relevance

Langerhans cells and other skin dendritic cells are critical components of the immune system in the skin. They are important in generating immune responses against invading pathogens, in the development of skin autoimmune diseases and in preventing responses to commensal skin pathogens. We are proposing to use Langerhans cell deficient mice that we have recently developed to investigate the precise molecular mechanisms that underlie the function of these cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR056632-01A1
Application #
7662020
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
1
Fiscal Year
2009
Total Cost
$332,200
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Dermatology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Kashem, Sakeen W; Igyártó, Botond Z; Gerami-Nejad, Maryam et al. (2015) Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Immunity 42:356-66
Tassi, Ilaria; Rikhi, Nimisha; Claudio, Estefania et al. (2015) The NF-κB regulator Bcl-3 modulates inflammation during contact hypersensitivity reactions in radioresistant cells. Eur J Immunol 45:1059-68
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Scholz, Felix; Badgley, Brian D; Sadowsky, Michael J et al. (2014) Immune mediated shaping of microflora community composition depends on barrier site. PLoS One 9:e84019
Igyarto, Botond Z; Kaplan, Daniel H (2013) Antigen presentation by Langerhans cells. Curr Opin Immunol 25:115-9
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Flamar, Anne-Laure; Zurawski, Sandra; Scholz, Felix et al. (2012) Noncovalent assembly of anti-dendritic cell antibodies and antigens for evoking immune responses in vitro and in vivo. J Immunol 189:2645-55
Haley, Krystal; Igyarto, Botond Z; Ortner, Daniela et al. (2012) Langerhans cells require MyD88-dependent signals for Candida albicans response but not for contact hypersensitivity or migration. J Immunol 188:4334-9
Kaplan, Daniel H; Igyarto, Botond Z; Gaspari, Anthony A (2012) Early immune events in the induction of allergic contact dermatitis. Nat Rev Immunol 12:114-24

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