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Robert L. Hendricks, Sophia S. Jeon, Anthony J. St. Leger, Thomas L. Cherpes; Regulation Of CD8+ T Cell Exhaustion During Herpes Simplex Virus Type 1 (HSV-1) Latency In Trigeminal Ganglia. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3142.
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© ARVO (1962-2015); The Authors (2016-present)
HSV-1 establishes latent infections in sensory neurons within the trigeminal ganglion (TG), which are maintained in part through immunesurveillance by CD8+ T cells. In C57BL/6 (B6) mice, half of the TG-resident CD8+ T cells are specific for an immunodominant epitope on HSV-1 glycoprotein B (gB498-505-CD8) and remain functional during latency. The other half are specific for HSV-1 subdominant epitopes (SD-CD8), divide more rapidly in vivo, up-regulate expression of the inhibitory PD-1 receptor, and become functionally exhausted during latency. The purpose of this study was to determine how exhaustion is selectively maintained in SD-CD8 and if recovery from exhaustion would result in better protection.
Wild type B6 mice, B6 mice lacking a ligand for the inhibitory PD-1 receptor (B7H1-/-), or bone marrow chimeras (wild type B6 bone marrow into B7H1-/- mice) received HSV-1 corneal infections. During HSV-1 latency (>30 days post infection) mice were not treated or were treated with anti-IL-10 receptor mAb or with BrdU; TG were excised, dispersed, and the frequency and function of CD8+ T cells and B7H1+ neurons was determined by flow cytometry and in ex vivo TG cultures. HSV-1 genome copy number was determined by real time PCR.
B7H1+ neurons have a higher copy number/cell of latent HSV-1 than B7H1- neurons. The absence of the B7H1 on neurons was associated with a dramatic selective expansion of PD-1+ SD-CD8 due to increased survival. Anti-IL-10R antibody treatment increased the number of PD-1+ and PD-1- SD-CD8 due to increased proliferation, resulting in an increase of functional SD-CD8. The lack of B7H1, or blocking the IL-10R caused a modest decrease, or increase, respectively in the absolute number of gB498-505-CD8; and neither influenced gB498-505-CD8 function. The increased number of functional SD-CD8 following in vivo IL-10R blockade resulted in significantly better CD8+ T cell protection from HSV-1 reactivation in ex vivo TG cultures.
It appears that SD-CD8 receive greater stimulation during latency resulting in higher proliferation and increased expression of PD-1, which interacts with B7H1 on neurons to limit SD-CD8 accumulation. Blockade of IL-10R during latency increases expansion of functional SD-CD8, resulting in increased CD8+ T cell protection from HSV-1 reactivation, providing a potential means of reducing the rate of recurrence of herpetic eye disease.
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