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-gamma 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-gamma receptors (IFN-gamma R+) and Qa 1 responds to IFN-gamma, but Qa 1 engagement of CD94/NKG2a blocks LG exocytosis by CD8+ T cells; (2) another neuronal subset is responsive to LG because it lacks Qa 1 and is refractory to IFN-gamma because it also lacks IFN-gamma R. In the latter subset, LG appear to provide a nonlethal block of viral reactivation.