The tetramer model: a new view of class II MHC molecules in antigenic presentation to T cells

Crystallographic studies suggest a plausible divalent interaction between T-cell receptor (TCR) and MHC class II molecules. In addition, biochemical data suggest that these divalent MHC molecules are preformed at the membrane of the antigen-presenting cell. The tetramer model is based on these preformed tetrameric class II molecules that can be loaded with identical or different peptides in their two grooves. This enables divalent class II molecules to deliver two different messages to T cell: 1) a two-peptide message, in which the tetramer with two identical peptides is able to cross-link two TCRs triggering full activation of a T cell. At the thymic level we propose that this message induces negative selection; or 2) a one-peptide message: only one of the peptides loaded in the class II tetramer is able to interact with that TCR. This message would be involved in triggering partial activation phenomena in mature lymphocytes, whereas in thymocytes this message would mediate positive selection. Since high concentrations of a peptide would favor the load of tetramers with identical peptides, the tetramer could therefore be viewed as a quantitative-qualitative transducer that would trigger different responses depending on the concentration of antigenic peptides.