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 #
5R01AI072571-07
Application #
8601039
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
2014-01-01
Budget End
2014-12-31
Support Year
7
Fiscal Year
2014
Total Cost
$356,038
Indirect Cost
$131,038
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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Lau, Colleen M; Nish, Simone A; Yogev, Nir et al. (2016) Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses. J Exp Med 213:415-31

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