Proper control of the immune system is critical to human health. A hypersensitive immune system can lead to allergies and autoimmune disease, whereas impairment of the immune system leaves an individual susceptible to infections and even cancers. Dendritic cells (DCs) play an important role in ensuring proper regulation of the immune system. In response to pathogens, DCs rapidly alter their phenotype to limit the spread of infection, and initiate an adaptive immune response. DCs are also involved in preventing autoimmunity by maintaining self tolerance. It is now understood that DCs are not a homogeneous population of cells. They are comprised of functionally distinct subsets with different abilities to process antigens, respond to environmental stimuli, and engage distinct effector lymphocytes. DC subsets include the CD8+ DCs that are specialized in the cross-presentation of cell associated antigens to CD8+ T cells, and plasmacytoid DC (pDC), which help to establish an antiviral state through the rapid secretion of high amounts of interferon alpha. While we now appreciate that DCs are a heterogeneous population, little is known about the mechanisms that drive DC lineage commitment and differentiation, as well as the mechanisms that control functional specialization. Our preliminary profiling data and functional analysis have led us to hypothesize that specific microRNA (miRNA) play a key role in regulating DC identity. Indeed, when we knocked out a single miRNA specifically in DCs we observed a significant reduction in the number of pDCs, but not other subsets in mice, and the pDCs had a major reduction in their functional response to TLR stimulation. Here, we propose studies aimed at better understanding how this miRNA controls pDC development and function, including studies to identify the relevant targets of this miRNA (Aim 1). We will also investigate the role of two other miRNA that we identified through profiling studies to be differentially expressed between DC subsets (Aim 2). To do this, we will use a state-of-the-art miRNA decoy vector system that we generated, which enables stable inhibition of a miRNA in mouse DCs in vivo and in human DCs in culture. Finally, we will address a broader question of how miRNAs themselves are regulated in DCs using a novel, functional assay that we developed, which permits high resolution assessment of each miRNA's cellular activity (Aim 3). We have focused our efforts on eliciting the role of miRNAs in DCs because these small non-coding RNAs are known to play a role in controlling cell identity, and because the discovery of relevant miRNAs can be used to uncover other genes and pathways that are important to DC function through the identification of the miRNA's regulatory targets. Thus, our studies will not only provide new insight into the role of specific miRNAs, but they will also reveal other genes involved in the regulation of DCs. This, in turn, will help to find potential new causes of immune dysfunction, and to supply new strategies to enhance or subdue immune responses for the treatment of diseases, and in the aid of vaccine development.

Public Health Relevance

Dendritic cells are crucial for controlling infections and for proper regulation of the immune system. The purpose of this study is to identify regulators of dendritic cell development and function. This is of major relevance for discovering the genetic factors that can contribute to autoimmune and inflammatory disease, and will potentially benefit the design of better viral and cancer vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI104848-05
Application #
9264490
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Jiang, Chao
Project Start
2013-05-24
Project End
2018-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Agudo, Judith; Park, Eun Sook; Rose, Samuel A et al. (2018) Quiescent Tissue Stem Cells Evade Immune Surveillance. Immunity 48:271-285.e5
Strub, Thomas; Ghiraldini, Flavia G; Carcamo, Saul et al. (2018) SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling. Nat Commun 9:3440
Salmon, Hélène; Idoyaga, Juliana; Rahman, Adeeb et al. (2016) Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. Immunity 44:924-38
Kidd, Brian A; Wroblewska, Aleksandra; Boland, Mary R et al. (2016) Mapping the effects of drugs on the immune system. Nat Biotechnol 34:47-54
Price, Jeremy G; Idoyaga, Juliana; Salmon, Hélène et al. (2015) CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation. Nat Immunol 16:1060-8
Zitvogel, Laurence; Galluzzi, Lorenzo; Viaud, Sophie et al. (2015) Cancer and the gut microbiota: an unexpected link. Sci Transl Med 7:271ps1
Agudo, Judith; Ruzo, Albert; Park, Eun Sook et al. (2015) GFP-specific CD8 T cells enable targeted cell depletion and visualization of T-cell interactions. Nat Biotechnol 33:1287-1292
Lavin, Yonit; Mortha, Arthur; Rahman, Adeeb et al. (2015) Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol 15:731-44
Nair-Gupta, Priyanka; Baccarini, Alessia; Tung, Navpreet et al. (2014) TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation. Cell 158:506-21
Lavin, Yonit; Winter, Deborah; Blecher-Gonen, Ronnie et al. (2014) Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159:1312-26

Showing the most recent 10 out of 14 publications