Plasmacytoid dendritic cells (pDCs) are distinct immune cells that rapidly secrete massive amounts of type I interferon (interferon ?/?, IFN) in response to nucleic acids that enter the endosomal compartment. Virus-induced IFN production by pDCs is critical for the control of viral infections, whereas aberrant pDC activation is associated with autoimmune diseases. Thus, pDCs represent a key innate immune lineage and an important target for immunotherapy. The pDCs appear related to conventional dendritic cells (cDCs) yet exhibit many properties of lymphocytes;hence the molecular basis of pDC development and lineage identity has been poorly understood. In the first cycle of the award, we have identified E protein transcription factor E2-2 as an essential and specific regulator of pDC development and maintenance. We proposed a model whereby pDCs develop in a common pathway with cDCs but get diverted into a distinct "lymphocyte-like" state by the induction of E2-2 and repression of its inhibitor Id2. We will now characterize the specificity, mechanism and functional targets of E2-2 activity in the pDC lineage.
In Aim 1, we will test the function of a pDC-specific E2-2 isoform and simultaneously visualize E2-2 and Id2 expression in single cells during pDC development.
In Aim 2, we will characterize a transcriptional co-repressor that may function together with E2-2 to inhibit Id2 expression and promote pDC development and functionality.
In Aim 3, we will characterize a novel pDC-specific transcription factor that contros the migration and homeostasis of peripheral pDCs. Collectively, these studies would further elucidate the unique lineage identity of pDCs, and characterize the molecular basis of pDC development and function in the steady state, antiviral immune responses and autoimmunity.

Public Health Relevance

Plasmacytoid dendritic cells (pDCs) represent distinct immune cells that rapidly secrete type I interferon (interferon ?/?, IFN) in response to viral infection, whereas their hyperactivation is involved in autoimmunity. We are studying the molecular basis of pDC development and function, with the goal of identifying potential targets for therapeutic immunomodulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI072571-06A1
Application #
8504195
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Palker, Thomas J
Project Start
2007-12-15
Project End
2017-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
6
Fiscal Year
2013
Total Cost
$370,602
Indirect Cost
$135,602
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
Sisirak, Vanja; Ganguly, Dipyaman; Lewis, Kanako L et al. (2014) Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. J Exp Med 211:1969-76
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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