Abstract
Abstract CD8 T cells that reside in the trigeminal ganglia (TG) of HSV-1 latently infected mice maintain viral latency through persistent interaction with infected neurons. Interestingly, CD8 T cells in TG of C57BL/6 mice exhibit a 1:1 ratio of cells recognizing subdominant versus an immunodominant (gB498-505) HSV-1 epitope. We investigated the role of Programmed Death-1 (PD-1) and its ligand, PD-L1 (B7-H1) in determining this ratio. We found that subdominant CD8 T cells in the TG 1) preferentially express PD-1, 2) are functionally compromised, and 3) proliferate and undergo apoptosis at a higher rate than gB498-505-specific CD8 T cells. Moreover, PD-L1 is preferentially expressed on neurons with a high latent viral load, and its expression is regulated by interferon-γ. In B7-H1-/- mice and bone marrow chimeras lacking PD-L1 only on parenchymal cells, the ratio of subdominant cells to gB498-505-specific cells was dramatically increased (4:1). This was due to increased survival of PD-1+ subdominant CD8 T cells that remained non-functional, and did not augment CD8 T cell protection from HSV-1 reactivation in ex vivo TG cultures. We conclude that PD-1/PD-L1 interaction regulates the survival, but not the function of CD8 T cells specific for subdominant HSV-1 epitopes in latently infected TG. Blocking this interaction alone is not sufficient to reduce HSV-1 reactivation from latency, but might be effective if combined with blockade of other suppressor molecules.
Published Version
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