The adaptive immune response protects us from infection in a world of pathogens that is forever evolving new variants. As the system is built on the generation of an open repertoire of receptors, the recognition of self is unavoidable, and is guarded against by deletion during lymphocyte development of those cells that are specific for ubiquitous self antigens, and the silencing of those that are specific for self antigens only encountered after cells achieve functional maturity in the periphery. This silencing occurs when lymphocytes recognize antigens in the absence of suitable costimulatory molecules. By contrast, when the same cell encounters the same ligand on a cell that expresses costimulatory molecules, it will proliferate and differentiate into an effector cell. These effector cells mediate protective immunity when the antigen is carried by a pathogen, but they can mount autoimmune responses if the antigen is derived from self. The major costimulatory molecules for CD4 T cells appear to be B7 and B7.2 that bind to the CD28 and CTLA-4 receptors on the T cell. The signals from the TCR appear to be integrated with those from the costimulator receptor, and the T cell response depends on the precise nature of these signals, further conditioned by cytokines present in the environment of the responding cell. B cells can be viewed in a similar way, with the costimulatory molecule CD40 ligand and cytokines coming mainly from CD4 helper T cells determining the fate of the responding B cell. The TCR is not simply an on and off switch, since the precise way in which the TCR is ligated determines the differentiation of the T cell and can alter the effector responses of established T cell lines. Thus, the response capabilities of T cells are more flexible than originally believed, and much of this flexibility comes from the interplay of TCR signals and signs from the environment. If the biochemical nature of these differential signaling pathways were known, it might be possible to develop simple pharmacological agents capable of diverting T cell responses from harmful to innocuous by getting the T cell to reinterpret the signals it is receiving via its receptors.(ABSTRACT TRUNCATED AT 400 WORDS)