In the current study we compared the mitogenic responses of T cells from skin and nerve biopsies of leprosy patients with those of peripheral blood mononuclear cells (PBMC). Lymphocytes from these sources were cultured at < or = 100 cells/well in the presence of PHA, irradiated autologous feeder cells, and IL-2, and proliferation was assessed after 6 to 12 days. Whereas PBMC were capable of vigorous responses, the growth of cells from skin and nerve was markedly reduced. The diminished response was independent of the clinical status of leprosy patients and was also observed in skin-infiltrating lymphocytes from patients suffering from other disorders. Analysis of proliferative responses at 1 cell/well suggested both a reduction in precursor frequency and a decrease in mean burst size. Analysis of lymphokine production suggested that cultured cells from skin lesions had reduced IL-w and IL-4 production relative to PBMC generated under similar conditions. Equal numbers of CD3+ cells were present in each source, but lesion cells were enriched in CD45RA- "memory" T cells, as well as CD3+CD28+ T cells. However, these alterations in subpopulation distribution could not account for the substantial differences in proliferative potential. We conclude that significant differences exist in the activation potential of cells from different tissue sources.