The crystal structure of the human major histocompatibility complex (MHC) HLADR1 molecule1 and crystal structures of T-cell receptor (TCR) fragments2, 3 make tenable the hypothesis of a divalent interaction between tetrameric MHC class II and tetrameric TCR. But how these molecular interactions occur still remains to be elucidated. Brown et al. 1 proposed a synergistic, multisubunit assembly process, in which an initially small monovalent interaction between the TCR and class II would be amplified by formation of a stable complex of dimerized TCRs and dimerized class II molecules for full intracellular signalling. The recently described dimeric structure of the TCR Vα domain and the TCR ß-chain structure support the possibility of a (VαVß) 2 tetramer. Fields and Mariuzza4 argue for a cooperative model of class II binding to the TCR similar to that proposed by Brown1, but they attribute to the TCR the key role in directing assembly of the divalent complex. Following determination of the HLA-DR1 crystal structure1, further data supporting the existence of preformed tetrameric class II molecules have since been published5, 6. However, Fields and Mariuzza do not take into account these data and reject any model for T-cell activation in which preformed MHC tetramers participate, arguing that there is no known mechanism for generating tetramers with the same peptide in both binding grooves. We would like to discuss several points with regard to this argument previously suggested by Brown1. First, although we do not agree with the necessity for such a mechanism, its existence cannot be ruled out simply because such a mechanism is not known. Second, if the existence of preformed tetrameric class II molecules is proved, it is reasonable to search for a role for this divalent molecule, as discussed below. MHC class II tetramers can bear two identical peptides or two different peptides. We consider that this phenomenon opens