Type 1 Diabetes: A Promising Dialogue between Promiscuous T Cell Receptor and H-2D^b Peptide Complex

Obliteration of the beta cells mediated by CD8 T cells in the islets of Langerhans leads to the development of autoimmune disease, type 1 diabetes (T1D). During the kickoff of T1D, CD8 T cells play a pivotal role in the destruction of these pancreatic beta cells. The CD8 T cell clone AI4, previously isolated from the islets of a young diabetes-prone NOD mouse, is found to be the most pathogenic among the population of CD8 T cell clones. Multiple natural and synthetic ligands for AI4 have been identified. These ligands include an unusually short seven-residue peptide derived from the insulin A chain (InsA14-20 ) that is recognized by AI4 in the context of H-2Db but lacks a C-terminal anchor residue. High diabetogenic activity of AI4 is accredited to the promiscuity, or cross reactivity, of its T cell receptor (TCR). We adopted the structural biology studies for understanding the mechanism of cross-reactivity of the AI4 TCR with its multiple ligands. Unraveling the three-dimensional structure of H-2Db with AI4 ligands will help us to unveil the distinct mechanisms involved in the recognition and the cross-reactivity of the AI4 TCR. In previous studies, our group has already reported two structures of the H-2Db peptide complexes recognized by AI4. In our present work we have solved two additional structures of H-2Db with AI4 ligands and several others are in progress. In addition to these studies, we have cloned, expressed and purified the AI4 TCR in a soluble form, which should allow us to obtain its structure alone and in complex with its multiple ligands. Our approach to study the interaction of promiscuous TCRs with their multiple ligands will allow us to uncover the likely multiple mechanisms that underlie TCR cross-reactivity in autoimmunity.