Previous studies have demonstrated that interleukin-2 knockout (KO) mice exhibit alterations in hippocampal cytoarchitecture. Several lines of evidence suggest that these variations may result from immune dysregulation and/or autoimmunity. Thus, this study sought to compare adult IL-2 KO mice and wild-type littermates (8-12 weeks of age), the age where differences in hippocampal cytoarchitecture have previously been observed, for differences in measures of neuroimmunological status in the hippocampus. Furthermore, because IL-15 shares the same receptor subunits for signal transduction as IL-2 (IL-2/15Rbeta and gammac) that are enriched in the hippocampus and may induce inflammatory processes in IL-2 KO mice, we sought to test the hypothesis that IL-15 is elevated in the hippocampus of IL-2 KO mice. Compared to wild-type mice, IL-2 KO mice exhibited increased hippocampal protein concentrations of IL-15 as well as IL-12, IP-10, and MCP-1. These cytokine changes, however, did not correlate with levels in the peripheral circulation, and there were no T cells or an increase in MHCII-positive microglia in the hippocampus of IL-2 KO mice. Since elevated levels of certain inflammatory cytokines may impair hippocampal neurogenesis, we also tested the hypothesis that changes in neuroimmunological status would be associated with reductions in neurogenesis of neurons in the dentate gyrus of IL-2 KO mice. Contrary to this hypothesis, compared to wild-type mice, male IL-2 KO mice exhibited increased neurogenesis in both the infrapyramidal and suprapyramidal limbs of the granule cell layer of the dentate gyrus, differences that were not observed between females. These findings indicate that IL-2 gene deletion alters the neuroimmunological status of the mouse hippocampus through a dysregulation of cytokines produced by CNS cells, and in males, these changes are associated with increased hippocampal neurogenesis.