Complexes of antigen analogues and major histocompatibility complexes have been demonstrated to function as effective antagonists of the T cell receptor (TCR). It was observed that modification of any of the major T cell contact residues can create powerful TCR antagonists. Increasing similarity of antagonist to antigen structure resulted in increased capacity to act as a TCR antagonist up to a point beyond which the analogues themselves showed antigenicity. These data strongly suggested that peptide: TCR interaction with a certain low affinity may still be sufficient for engagement of the receptor but not for signalling, thus resulting in antagonism. It was found that the presentation of antagonistic peptides alone did not induce the formation of stable conjugates between antigen presenting cells and T cells, but rather that presentation of antigen was required to induce the initial interaction of APC with T cells in cell:cell conjugates. This antigen-dependent conjugate formation was not affected by the antagonist, while very early intracellular biochemical events such as PI turnover and CA2+ flux were inhibited.