The nature and location of cells responding to tumour necrosis factor-alpha (TNF-alpha) were investigated in situ by immunohistochemistry using monoclonal antibodies (mAb) directed against the p75 and p55 proteins of the TNF receptor. Receptor expression was found in the thymus and secondary lymphoid tissues. In the thymus the p75 receptor was confined to medullary lymphoblasts and dendritic cells, which co-stain with the Tac protein of the interleukin-2 (IL-2) receptor. In lymph nodes and other secondary lymphoid tissues, the p75 receptor was expressed on activated lymphocytes and interdigitating reticulum cells of the T-cell area, whereas the p55 receptor was confined to the germinal centre dendritic reticulum cells (DRC), which is the main site of TNF-alpha production. TNF receptor (TNFR) proteins were up-regulated in reactive hyperplasia together with increased TNF-alpha expression. Surprisingly, no TNFR was detectable on non-lymphoid tissues. The species specificity of these TNFR antibodies was high: whereas the antibodies cross-reacted with epitopes in non-human primates, no immunoreactivity was detected in lower animal species, e.g. dog, rabbit and rodents. The data presented suggest that TNF-alpha, which is produced by germinal centre DRC, might regulate an in vivo immune response through autocrine and paracrine pathways, e.g. through the p55 and p75 receptor proteins, which are expressed at different sites of the lymphoid tissue.