Increased levels of lipocortins occur in the nervous system in multiple sclerosis, in experimental autoimmune encephalomyelitis and experimental neuritis at the height of disease and decrease thereafter, suggesting their potential involvement in recovery from disease. We therefore investigated whether lipocortins may suppress activation of autoimmune T cells. Antigen-specific and growth factor-mediated proliferation of T cell lines reactive with myelin basic protein (MBP) was measured in the presence of recombinant lipocortin-1, -2, and -5, and natural bovine lipocortin-1 using various concentrations and incubation periods. We also employed an N-terminal lipocortin-1 peptide spanning aa 1-26, a proteolytic fragment of lipocortin-1 where the respective N-terminal region was clipped off, tested blocking with a neutralizing antibody, and investigated the effect of alkaline phosphatase treatment. Both human recombinant and bovine lipocortin-1 had a marked suppressive effect on T cell activation by MBP and the respective immunogenic peptide. When added at 3 micrograms/ml we observed up to 90% inhibition of T cell proliferation between day 2 and 3, but not at earlier time points of activation. The inhibitory effect of human lipocortin-1 was blocked after addition of a neutralizing antibody directed against lipocortin-1. Lipocortin-2 and -5, and the N-terminal peptide of lipocortin-1 were ineffective, whereas the fragment spanning residues 27-345 of lipocortin-1 retained full activity. Treatment of bovine lipocortin-1 with alkaline phosphatase did not alter immunosuppressive properties.