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One of the fundamental immunologic characteristics of systemic lupus erythematosus (SLE) is a depressed T cell proliferative response to various specific and nonspecific stimuli. Both intrinsic cellular defect(s) and inhibitory influences of humoral factors, e.g., antilymphocyte autoantibodies or immune complexes, have been postulated to underly this functional abnormality. Because patient serum can induce SLE-like T cell dysfunction in normal cells, an extrinsic mechanism is probably responsible, but the nature and site of action of this humoral activity has not been defined. This laboratory recently described a novel antibody specific for activated T cells in SLE, which raised the possibility that suppression of T cell proliferation by SLE serum involved antibodies directed to surface determinants expressed during the process of activation. In experiments to examine this concept further, relatively warm-reactive antibodies to T cell blasts were found to inhibit strongly the well-characterized T cell response to tetanus toxoid. These antibodies were distinct from conventional cold-reactive IgM antibodies to resting T cells, which exhibited little inhibitory activity. Inhibition involved noncytotoxic effects on early activation events at the level of the responding T cell, which markedly reduced the expression of receptors for interleukin 2. Inhibitory effects on antigen-pulsed macrophages or on T cells already committed to proliferate were not demonstrable. Anti-T blast antibodies were characteristic of active SLE and were detected only occasionally in patients with inactive disease or non-SLE rheumatic disorders. Although the exact antigenic specificity was not identified, considerable evidence was obtained against the presence of antibodies to Ia and certain other surface determinants of functional relevance. Our observations concerning the suppressive effects of anti-T blast antibodies in SLE serum on the T cell response to tetanus toxoid should provide new insight into mechanisms of in vivo T cell dysfunction in this and other immunologic disorders.