Plasmacytoid dendritic cells (PDC) represent a unique secretory cell type that plays a critical role in innate immune responses. PDC respond to virus-associated nucleic acids with a massive secretion of type I interferon (IFN), and therefore are often described as "natural interferon-producing cells". In addition, PDC are capable of differentiation into conventional antigen-presenting dendritic cells, and of activating a wide range of immune cell types. Because of their IFN-producing capacity, PDC are essential for the control of viral infections, whereas aberrant IFN secretion by PDC appears to be involved in autoimmune diseases. The PDC possess unique cellular and molecular features and gene expression patterns that facilitate their distinct homing and migration pattern, direct recognition of viruses, high-level IFN secretion and differentiation into dendritic cells. However, the molecular mechanisms that regulate lineage commitment, maturation, and function of PDC remain poorly understood. The overall goal of our research is to dissect the regulation of PDC development and function at the molecular level. In preliminary experiments, we identified candidate transcriptional and signaling mechanisms operating in the PDC.
In Specific Aim 1, we will analyze the role of basic helix-loop-helix transcription factors in PDC development and maintenance.
In Specific Aim 2, we will concentrate on Smad-mediated TGFb superfamily signaling in the PDC lineage. Altogether, these studies would elucidate the genetic network governing PDC development and function, and thus pave the way for immunotherapeutic approaches directed at the PDC. PROJECT NARRATIVE: The study is aimed at molecular and genetic analysis of plasmacytoid dendritic cells (PDC), a unique immune cell type that plays a major role in anti-viral immune responses and in autoimmunity. The elucidation of molecular mechanisms that govern PDC development and function would pave the way for novel therapeutic approaches targeting PDC function in infections and autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072571-05
Application #
8197152
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2007-12-15
Project End
2012-12-31
Budget Start
2011-12-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$312,025
Indirect Cost
$116,005
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Ghosh, Hiyaa S; Ceribelli, Michele; Matos, Ines et al. (2014) ETO family protein Mtg16 regulates the balance of dendritic cell subsets by repressing Id2. J Exp Med 211:1623-35
Ganguly, Dipyaman; Haak, Stefan; Sisirak, Vanja et al. (2013) The role of dendritic cells in autoimmunity. Nat Rev Immunol 13:566-77
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Reizis, Boris; Colonna, Marco; Trinchieri, Giorgio et al. (2011) Plasmacytoid dendritic cells: one-trick ponies or workhorses of the immune system? Nat Rev Immunol 11:558-65
Reizis, Boris; Bunin, Anna; Ghosh, Hiyaa S et al. (2011) Plasmacytoid dendritic cells: recent progress and open questions. Annu Rev Immunol 29:163-83
Bar-On, Liat; Birnberg, Tal; Lewis, Kanako L et al. (2010) CX3CR1+ CD8alpha+ dendritic cells are a steady-state population related to plasmacytoid dendritic cells. Proc Natl Acad Sci U S A 107:14745-50
Sathaliyawala, Taheri; O'Gorman, William E; Greter, Melanie et al. (2010) Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity 33:597-606
Reizis, Boris (2010) Regulation of plasmacytoid dendritic cell development. Curr Opin Immunol 22:206-11

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