Receptor proximity, not intermolecular orientation, is critical for triggering T-cell activation

Engagement of antigen receptors on the surface of T-cells with peptides bou nd to major histocompatibility complex (MHC) proteins triggers T-cell activ ation in a mechanism involving receptor oligomerization. Receptor dimerizat ion by soluble MHC oligomers is sufficient to induce several characteristic activation processes in T-cells including internalization of engaged recep tors and up-regulation of cell surface proteins. In this work, the influenc e of intermolecular orientation within the activating receptor dimer was st udied. Dimers of class II MHC proteins coupled in a variety of orientations and topologies each were able to activate CD4(+) T-cells, indicating that triggering was not dependent on a particular receptor orientation. In contr ast to the minimal influence of receptor orientation, T-cell triggering was affected by the inter-molecular distance between MHC molecules, and MHC di mers coupled through shot-ter cross-linkers were consistently more potent t han those coupled through longer cross-linkers. These results are consisten t with a mechanism in which intermolecular receptor proximity, but not inte rmolecular orientation, is the key determinant for antigen-induced CD4(+) T -cell activation.