Nerve growth factor (NGF) is a neurotrophic protein essential for the maintenance and growth of peripheral sympathetic neurons and basal forebrain cholinergic neurons. Recently, NGF has also been shown to have effects on cells of the immune system. In a search for extra neural sources of NGF, we detected NGF-specific mRNA in mouse T lymphocytes of both the CD4+ and CD8+ phenotypes with the use of an RNase protection assay, PCR, and DNA sequence analysis. In CD4+ cells, NGF was present in both Th1 and Th2 Ag-specific clones, but an increase of NGF-specific message was detected after antigenic stimulation only in Th2 clones. NGF mRNA was also detected in splenic B lymphocytes and in a cell line derived from a murine follicular center cell lymphoma. Translation into protein and secretion of NGF were demonstrated by Western blot analysis. The secreted NGF is in an active form capable of inducing differentiation of PC12 cells into sympathetic-like neurons. Furthermore, conditioned medium from clones or lines positive for NGF mRNA was capable of inducing p140 tyrosine kinase autophosphorylation in 3T3 fibroblasts transfected with cDNA encoding for the tyrosine kinase family NGF receptor. We conclude that lymphocytes synthesize and secrete NGF either as a para-autocrine factor acting on the immune system itself, or as a factor for the maintenance of peripheral neurons.