Regulation Of CD8+ T Cell Exhaustion During Herpes Simplex Virus Type 1 (HSV-1) Latency In Trigeminal Ganglia

Abstract

Purpose: : 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 (gB_498-505-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.

Methods: : 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.

Results: : 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 gB_498-505-CD8; and neither influenced gB_498-505-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.

Conclusions: : 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.

Keywords: immunomodulation/immunoregulation • herpes simplex virus • microbial pathogenesis: experimental studies