CD28 and CD152 have crucial yet opposing functions in T-cell stimulation, in which CD28 promotes but CD152 inhibits T-cell responses. Intriguingly, they share two ligands, CD80 and CD86, but at present there is no clear model for understanding whether a ligand will promote or inhibit responses. Current perceptions are based around the concept that CD86 is the initial co-stimulatory ligand based on its more abundant and earlier expression pattern; CD80 has a role following antigen-presenting-cell activation. We describe an alternative view in which CD80 is the initial ligand, responsible for maintaining aspects of immune tolerance through interactions with CD152. These inhibitory functions can then be over-ridden by the upregulation of CD86 on dendritic cells as a result of inflammatory stimuli, leading to immune activation.