Tenascin is a nonubiquitous extracellular matrix protein mainly expressed during morphogenesis in embryonal life. In adults it reappears in malignant tumors and during inflammation and tissue repair. Extracellular matrix proteins can alter cell morphology, adhesion, motility, differentiation, and growth. Since cells of the immune system can express receptors for extracellular matrix, we investigated the effects of tenascin on human monocytes and T and B lymphocytes. Tenascin inhibited monocyte adhesion to fibronectin and enhanced the LFA-1 (lymphocyte function-associated antigen 1)-dependent clustering of Epstein-Barr virus-transformed B cells. The physiological consequences of the effects of tenascin were studied in several T-cell activation models. Tenascin inhibited T-cell activation induced by a soluble antigen (tetanus toxoid), alloantigens, or the mitogen concanavalin A. However, T-cell activation with phytohemagglutinin, crosslinked anti-CD3 antibody, or a mixture of ionomycin and phorbol ester was not inhibited by tenascin. Tenascin did not prevent interleukin 2-dependent T-cell growth or the cytolytic activity of an antigen-specific CD4+ T-cell clone. These results suggest that tenascin alters the adhesion properties of human monocytes, B cells, and T cells. The in vitro immunosuppressive activity of tenascin might be due to abrogation of an accessory cell function at an early stage of the interaction between antigen-presenting cells and T cells.