Soluble mediators play an important role in the positive and negative regulation of immune reactions. This has been particularly well documented for T-B-cooperation in the humoral immune response to T-dependent antigens. T-helper cells produce a T-cell replacing Factor (TRF) upon mitogenic or antigenic stimulation. It provides the signal to antigen triggered B-cells to begin with active antibody synthesis and secretion and thus it is a positively regulating mediator. Additional functional and some structural characteristics of TRF are described. Antigen specific and non-specific suppressor factors seem to be involved in the negative regulation of immune responses. Thus, the communication between cells of the immune system is largely conducted via soluble signal substances.