Plasmacytoid dendritic cells (pDC), a distinct type of bone marrow-derived cell, play an important role in linking innate and adaptive immune responses. pDC are pivotal in the first line of defense against viral infections through recognitio of viruses by toll-like receptors as well as their ability to produce large amounts of type I interferons (IFN). In preliminary studies, we have discovered a novel population of resident pDC in the cornea. In vivo pDC depletion in our preliminary studies demonstrate that pDC are the major source of IFN-a in the cornea and play a protective role in the host defense in herpes simplex keratitis (HSK). Thus our results suggest that pDC are key participants in fighting viral keratitis, while preserving vision. Identifying specific functions of pDC in HSK and understanding the critical pathways of pDC and T cell migration in the cornea may provide new molecular targets for pharmacological intervention through immunotherapy. However, defining organ- and cell-specific molecular migratory mechanisms is critical, in order to inhibit cell subsets driving disease, without affecting leukocytes required for protective immunity. To address these questions, we have developed a new multiphoton intravital microscopy (MP-IVM) model to study pDC in intact corneas of living mice. This imaging approach uses transgenic mice, with fluorescent pDC, and fluorescent viruses, and will visualize pDC and viruses at subcellular resolution in living animals, allowing us to study their interaction with surrounding cells. Based on preliminary work and that up-regulation of organ-specific combination of vascular adhesion molecules and chemokines regulate pDC and T cell recruitment to the cornea and subsequent migration of pDC from the cornea in inflammation and infection. We further hypothesize that pDC are protective to the cornea in HSK through local corneal IFN-? and TNF-? production and migrate to distinct areas of the dLN after activation in HSK, where they mediate differentiation pathways of CD4+ T cells to T regulatory or T helper (Th)17 cells through IFN-? and IL-6 production. pDC will be studied to investigate the traffic signals that guide them to normal and inflamed corneas and will be used to address the following two specific aims: 1.) To characterize corneal pDC and dissect the molecular mechanisms that mediate their recruitment and egress during inflammation;2.) To characterize corneal pDC and dissect the molecular mechanisms that mediate their recruitment and egress during inflammation. Identification of these critical pathways of cell migration to and from the cornea will provide new and highly specific molecular targets for pharmacological intervention in inflammatory, infectious, alloimmune and autoimmune diseases. Few effective anti-inflammatory drugs have emerged over the last decades in the ophthalmic field and an urgent need for new drugs exists. HSK is a leading cause of blindness. Effective therapy for HSK would significantly reduce visual impairment, increase productivity, and reduce the burden of treating HSK.

Public Health Relevance

Herpes simplex virus keratitis is the most common cause of corneal blindness in the developed world due to corneal scarring and permanent vision loss. Plasmacytoid dendritic cells are the most recent addition to armamentarium of the immune system and have a critical role in antiviral immunity, as they can directly sense viruses in peripheral tissues, and educate other protective players of the immune system, called T cells. Defining organ- and cell-specific molecular migratory mechanisms is critical, in order to inhibit cell subsets driving disease, without affecting leukocytes required for protective immunity. Identification of critical pathways of plasmacytoid dendritic cell migration in the cornea and thei role in herpetic eye disease may provide new molecular targets for pharmacological intervention in infectious, inflammatory, and autoimmune corneal diseases through highly innovative specific strategies for immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY022695-01A1
Application #
8506240
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
2013-09-01
Project End
2018-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$492,500
Indirect Cost
$242,500
Name
Schepens Eye Research Institute
Department
Type
DUNS #
073826000
City
Boston
State
MA
Country
United States
Zip Code
02114