Immunological tolerance can be achieved by several mechanisms including suppressor cells, soluble factors, and neurohormonal mediators. On the cellular level, we isolated a population of CD8+CD28- T cells capable of inhibiting anti-CD3 mAb-induced proliferation of autologous peripheral blood mononuclear cells in an HLA-I nonrestricted manner via production of IFN-gamma and IL-6. Interestingly, CD8+CD28- T cells from systemic lupus erythematosus patients with active disease do not display this inhibitory activity and show a marked imbalance between inhibitory (IL-6) and stimulatory (IL-12) cytokines. For soluble factors, we studied soluble HLA molecules (sHLAs) and double-stranded DNA (ds-DNA). Soluble HLA-I (sHLA-I) molecules induce soluble Fas ligand (sFasL) secretion and trigger apoptosis in phytohemagglutin (PHA)-activated Fas+ T cells. Double-stranded DNA binds to HLA-II molecules and inhibits HLA-II-mediated antigen presentation. On the neurohormonal side, we focused our attention on the immunological activity of corticosteroids (CTSs). CTSs inhibit recirculation of CD4+ T cells, suppress the proliferation and immunological function of activated T cells, and induce apoptosis of activated lymphocytes. Taken together, these data suggest the presence of a complex network of immunoregulatory mechanisms in which CTSs play a strong role supporting their recognized efficacy in the treatment of inflammatory and immunological diseases.