A T cell requires two independent signals before it becomes fully activated. Signal one is delivered when the T cell receptor binds its specific peptide-MHC complex on an antigen-presenting cell. Signal two, called costimulation, is delivered when CD28 on the T cell binds CD80 or CD86 on the same antigen-presenting cell. If a T cell receives signal one without signal two, it does not become activated; it enters a state called anergy, in which it becomes functionally unresponsive to subsequent antigen encounter. B cells follow the same logic: antigen binding to the B cell receptor provides signal one, while costimulation from helper T cells or complement receptors provides signal two. The two-signal requirement means that antigen recognition alone is not sufficient to trigger a destructive response. Costimulation is the checkpoint that confirms the antigen is being presented in a context that warrants activation.
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Look at the two pathways shown. On the left, the T cell receptor binds peptide-MHC and delivers signal one. On the right, CD28 on the T cell binds CD80 or CD86 on the antigen-presenting cell and delivers signal two. When both signals arrive together, the T cell activates. When only signal one arrives, the T cell becomes anergic, meaning it is functionally switched off rather than turned on. This is the checkpoint that prevents a response to antigen presented without proper context.
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