n important issue in immune cell biology is how some receptors can deliver qualitatively different signals to cells, depending upon the bound ligand. Here, we consider the T-cell receptor (TCR), which in response to some ligands delivers a negative signal to the cell, whereas other ligands will activate the cell 1ร4 . Therefore the TCR has to signal to the cell not only that it has engaged a ligand, but also which ligand has been engaged.
Altered ligands for the TCR are created using either altered peptide ligands (APLs), in which amino acid residues are mutated 5 , or by using wild-type peptide in the context of a mutant major histocompatibility complex (MHC) molecule 3,4,6 . These altered ligands can act as partial agonists, antagonists or null ligands. Partial agonists can suboptimally activate T cells such that, for example, interleukin 4 (IL-4) and B-cell help are stimulated, but proliferation is not 7 . Subsequently, these T cells cannot respond to wild-type peptide on fresh antigen-presenting cells (APCs) for up to ten days 8 .
Antagonists prevent the activation of T cells when presented simultaneously with wild-type peptide 9 . This is not due to classical competitive antagonism with wild-type peptide for binding to MHC, as antagonists can block stimulation by superantigen, which binds at a site distant from the peptide groove of the MHC molecule 10 . Furthermore, some antagonists block the response to wildtype peptide in concentrations 10 3 ร10 4 times lower than that required for competitive inhibition 11 .