Molecular associations and microdomains in antigen-presenting cell-T-cell interactions

Protein-protein interactions are utilized by the cell for almost all biological processes. Homotypic associations-physical associations between related proteins-are commonly employed as regulatory mechanisms with diverse physical and biological outcomes. X-ray crystallography has helped to reveal such protein-protein interactions. The field of antigen presentation has been especially helped by X-ray crystallography. For example, HLA-DR, CD4, and the TCR have all been crystallized as individual homodimers. One of the surprises from the early crystallographic work on MHC class II molecules was the observation that individual class II molecules existed as dimers of dimers or "superdimers," as they were called. Their existence was later confirmed by biochemical and single-cell fluorescent imaging methods. A "noninvasive" fluorescent-based technique confirmed the existence of MHC class II dimers of dimers on human living antigen-presenting cells (APCs) and ruled out potential artifacts that could have been introduced during the preparation of material for either crystallographic or biochemical studies. Little functional information has emerged so far as to the physiological significance of the MHC class II dimers of dimers. In this article, we review all the past and the latest advances in the field, taking into account the discovery of the immunological synapse and supramolecular activation clusters, and discuss the possibility of different molecular associations and microdomains involved in APC-T-cell recognition.