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R. L. Hendricks, G. M. Frank; CD11cHigh Dendritic Cells Control the Innate Immune Response That Clears Herpes Simplex Virus Type 1 From the Cornea. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2015.
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CD11chigh dendritic cells (DC) regulate both adaptive and innate immune responses. Clearance of HSV-1 from infected corneas appears to be primarily mediated by an innate immune response comprised of natural killer (NK) cells and neutrophils, with an unknown contribution of CD11clow PDCA1+ plasmacytoid DC (pDC), a major source of type 1 interferon in infected mice. The purpose of this study was to elucidate the role of DC in regulating the infiltration of NK cells, neutrophils, and pDC and viral clearance from HSV-1 infected corneas.
CD11c DTR mice were treated subconjunctivally or systemically (intraperitoneal) with diphtheria toxin (DT) 1 day before HSV-1 corneal infection to transiently deplete DC, or were additionally DT treated at 2 days post infection (dpi), and 5 dpi to continuously deplete DC. Confocal microscopic examination confirmed depletion of CD11chigh (EGFP+) cells. Corneas were swabbed on alternate dpi and HSV-1 titers determined in a standard viral plaque assay. At 7 dpi corneas were dissected, the central cornea separated from the peripheral cornea using a 2 mm trephine, the cells were dispersed with collagenase, and NK cells, pDC, and PMN were quantified in the peripheral and central cornea by flow cytometry.
A single local or systemic DT treatment at -1 dpi depleted CD11c+ DCs from the cornea through 3 dpi, and systemic (but not local) DT treatment depleted CD11c+ DCs from lymphoid organs through 3 dpi. Neither treatment depleted pDC from the cornea. Transient local and more profoundly systemic DC depletion significantly increased the HSV-1 titers in the cornea, and this effect was not augmented by continuous DC depletion. Transient local and systemic DC depletion, while not influencing migration of NK cells, pDC, or PMN into the peripheral cornea, did significantly reduce migration of NK cells and pDC, into the central cornea. Both treatments augmented migration of PMN into the central cornea.
These findings demonstrate that resident and/or early infiltrating corneal DC play a critical role in inducing the migration of NK cells and pDC into the central, but not the peripheral cornea. Failure of NK cells and pDC to accumulate in the central cornea is associated with impaired control of HSV-1 replication. Transient systemic DC depletion does not influence the capacity of NK cells to extravasate into the cornea as observed in other models. DC depletion augmented PMN migration into the central cornea, suggesting that these cells either are not required for viral clearance or require an activation signal from DC to function.
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