The effect of unilateral peripheral nerve lesions on the inflammatory response of experimental allergic encephalomyelitis (EAE) in rat central nervous system (CNS) was studied. Immunostaining for major histocompatibility complex (MHC) antigens and T-cell subsets demonstrated that MHC class I expression was markedly enhanced in as well as around axotomized motor neurons and that MHC class II expression was induced on several cells, probably microglial cells, in close proximity to the axotomized motor neurons. There was also a pronounced increase in interleukin 2 receptor-positive lymphocytes as well as T-cells and the T-cell subsets on the injured as compared to the non-injured contralateral side. These effects were present particularly in the initial phase of EAE and persisted for several weeks. The results suggest that neurons may communicate immunoregulatory signals to their microenvironment and that retrograde axonal signals from the distant periphery may alter the immune response locally within the CNS.