Making the Most of Major Histocompatibility Complex Molecule Multimers: Applications in Type 1 Diabetes

Figure 1

Schematic representation of the effects of toxic pMHCI tetramer administration to NOD mice. Clockwise from upper left: toxic moieties, such as saporin, can be linked to pMHCI multimers that are specific for diabetogenic CTL before being delivered to prediabetic NOD mice. Toxic pMHCI tetramers can access inflamed islets where cognate CTLs are present. Insulitis involves numerous autoreactive immune cell subsets that act in concert to potentiate diabetogenic CTL and destroy β cells. However, pMHCI multimers can deliver saporin to diabetogenic CTL clonotypes and induce apoptosis in an antigen-specific manner. Cognate TCR interacting with saporin-conjugated pMHCI results in uptake of the tetramer into the lysosome of the CTL. In the lysosome, the toxic pMHCI tetramer is disassociated, allowing the freed saporin molecules to escape these organelles. Saporin is a potent ribosome-inactivating toxin that can perform multiple rounds of ribosome disabling, ultimately leading to apoptosis of the CTL and therein preventing further β cell damage by the targeted diabetogenic clonotype.