Sensory neurons regulate the effector functions of CD8⁺ T cells in controlling HSV-1 latency ex vivo

We provide evidence that sensory neurons regulate the effector functions and phenotype of CD8⁺ T cells during active immunosurveillance of HSV-1 latency. Low-level viral gene expression in latently infected sensory ganglia gives rise to a unique, functionally active CD8⁺ T cell population. Surprisingly, distinct neuronal subsets require different CD8 effector mechanisms to maintain viral latency, with some requiring IFN-γ and others requiring lytic granules (LG). This nonredundant efficacy of CD8 ⁺ T cell effector mechanisms in maintaining viral latency is explained as follows: (1) a subset of neurons that expresses IFN-γ receptors (IFN-γR⁺) and Qa1 responds to IFN-γ, but Qa1 engagement of CD94/NKG2a blocks LG exocytosis by CD8⁺ T cells; (2) another neuronal subset is responsive to LG because it lacks Qa1 and is refractory to IFN-γ because it also lacks IFN-γR. In the latter subset, LG appear to provide a nonlethal block of viral reactivation.