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J. E. Knickelbein, R. L. Hendricks; Expression and Function of Natural Killer (NK) Cell Receptors in Ocular HSV-1 Infection. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3874.
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Innate immune cells, including NK cells, clear replicating HSV-1 from acutely infected ganglia, while CD8 T cells of the adaptive immune response maintain HSV-1 neuronal latency through nonlytic mechanisms involving both cytokine secretion and lytic granule release. NK cell receptors regulate effector functions of both NK and certain CD8 T cells. Different members of this family of receptors act to either augment (e.g. NKG2D) or inhibit (e.g. NKG2A) NK and CD8 T cell activity. The current study aims to define the expression and function of NK cell receptors on NK and CD8 T cells following corneal HSV-1 infection.
The corneas of various strains of mice were scarified and topically infected with HSV-1. Flow cytometry was employed to quantify and phenotype NK and CD8 T cells from dispersed latently infected trigeminal ganglia (TG). Standard viral plaque assays and PCR analysis for viral genome copies were used to quantify viral infection.
NK cells within noninfected TG predominantly express the inhibitory NKG2A receptor, suggesting suppression of cytolytic function against non-regenerating neurons. NK cell infiltration into HSV-infected TG peaks at 5 days post-infection (dpi). Upon infection, NK cells expression of NKG2A declines, while activating NKG2D receptor expression rises to a climax at 5 dpi. The number of TG-resident NK cells and percentage expressing NK receptors returns to naïve levels by 35 days post-infection. TG from perforin- and granzyme B-deficient mice contain significantly more replicating virus at 5 dpi compared to WT mice demonstrating the importance of NK cell lytic granule function. Infiltration of CD8 T cells, and their expression of NKG2D, into HSV-1-infected TG peaks at 14 dpi. In a trend similar to NK cells, a greater population of CD8 T cells express NKG2A compared to NKG2D by 35 dpi. Qa-1, a non-classical MHC class 1 molecule and NKG2A ligand, has been shown to be upregulated on neurons following HSV-1 infection. However, Qa-1-deficient mice showed no significant differences from wild-type mice following ocular HSV-1 infection in terms of rate of viral clearance from infected corneas, viral titers in acutely infected TG, viral genome copy number in latently infected TG, or rate or magnitude of viral reactivation in ex vivo cultures of latently infected TG.
The absence of inhibitory Qa-1-mediated NKG2A signaling does not to alter the course of acute or latent HSV-1 infection suggesting the possibility of other NKG2A ligands. Further studies are required to determine the role for NKG2A and NKG2D in controlling viral clearance and pathology within HSV-1-infected TG.
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