Immune tissues are known to be innervated by the sympathetic nervous system, but little is known of what directs the innervation to specific tissue compartments. This report examines the sympathetic innervation of immune tissues in transgenic mice that overexpress nerve growth factor (NGF) in skin and other epithelial structures. NGF transgenic mice exhibited dramatic hyperinnervation in the splenic marginal zone, and the medulla and capsule of peripheral lymph nodes. In contrast, the transgenic mesenteric lymph nodes showed no hyperinnervation. This difference correlated with the location of these nodes; peripheral lymph nodes drain skin where the transgene was expressed while mesenteric lymph nodes drain non-transgene-expressing structures. In addition, the level of innervation correlated with the level of NGF peptide content as assayed by ELISA (3- and 13-fold increase in transgenic spleen and axillary lymph nodes, respectively; no increase in mesenteric nodes) and immunocytochemistry. RT-PCR showed that the NGF transgene was not being expressed in the immune tissues, suggesting that immune tissues can concentrate transgene-produced NGF. It was also demonstrated that the change in innervation had functional consequences. The mitogen response to concanavalin A (ConA) by spleen cells was decreased in the transgenics suggesting that elevated catecholamines or NGF can modulate the proliferative response of these cells. These mice demonstrate that NGF can modulate the sympathetic innervation and function of the immune system.