Previous studies have shown that effective T-cell activation requires the engagement of the T-cell receptor complex with MHC-peptide, in parallel with co-stimulation via cell surface adhesion molecules. Blocking these co-stimulatory interactions, in particular the signal transduction via the CD28 molecule, inhibits T-cell activation in vitro and induces T-cell clones into a state of unresponsiveness, termed T-cell anergy. Recent studies have examined the therapeutic effects of treating mice with CD28-B7 antagonists and highlighted the complexity of the CD28 co-stimulatory pathway, as illustrated by the finding that multiple cross-binding ligands for the CD28 and B7 molecules exist that may differentially regulate immune responses.