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Paul R Kinchington, Benjamin Treat, Sarah Bidula, Robert L Hendricks; Ganglionic CD8 T Cells Associated with HSV-1 Latency in the Murine Ocular Infection Model Show Increased Functionality in the Absence of Immunodominant CD8s and are Entirely HSV-1 Specific. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4060.
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© ARVO (1962-2015); The Authors (2016-present)
The murine ocular HSV-1 infection model has provided insight into immune control of HSV latency and ocular disease. Following HSV-1 ocular infection, trigeminal ganglia (TG) are infiltrated by activated CD8 T cells, peaking at the onset of HSV-1 latency, which contracts to a low but stable persisting level that can block HSV reactivation. HSV-1 induced CD8 T cells in C57Bl6 mice are remarkably skewed by immunodominance, with >50% of CD8s (gB-CD8) recognizing a single epitope on glycoprotein B (gB498-505). The gB-CD8 T cells in the HSV-1 latently infected TG are activated and functional, while the non-gB CD8 T cells show an exhausted phenotype. Given that immunodominance of gB-CD8s is maintained at latency and shows most functionality, we asked how CD8 T cell populations develop and function at latency to HSV-1 lacking the gB498-505 epitope.
Recombinant HSV-1 (HSV S1L) were developed with mutation of the gB498-505 epitope. TG, DLN and splenic CD8 T cell responses at acute (day 8 pi) and latent (day 33 pi) stages were characterized by flow cytometry after staining for CD45, CD3, CD8 and HSV-1 tetramers. Functionality of CD8 T cell hierarchies were addressed by stimulating with peptides of the known HSV-1 CD8 T cell epitopes, followed by staining of CD8 for production of IFNγ.
HSV S1L induced a similar sized CD8 T cell inflitrate to that for wt HSV-1, but lacked the gB498-505- dominated CD8 T cell response to wt HSV-1. The compensation was due to increase of CD8s directed to most subdominant epitopes. In contrast to latency of wt HSV-1 where gB CD8s are functional and non-gB CD8s demonstrate an exhausted phenotype, the entire TG associated CD8 T cell population induced by HSV-1 S1L at latency could be stimulated by CD8 subdominant peptides. The resulting CD8 hierarchy in the TG showed preferential retention of CD8s to certain subdominant epitopes.
This work establishes that: (1) the ganglionic CD8 T cell populations associated with HSV-1 at the latency is all HSV-1 specific and; (2) the hierarchy and functional state of latency-associated CD8 T cells is influenced by the presence of immunodominant gB-CD8s. This work has important consequences in the design of vaccines aimed at stimulating a broadly functional CD8 T cell response
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