Compensatory Mechanisms Allow Undersized Anchor-Deficient Class I MHC Ligands To Mediate Pathogenic Autoreactive T Cell Responses
| Autor: | David V. Serreze, P. Rajesh Kumar, Dibyendu Samanta, Teresa P. DiLorenzo, Thomas W.H. Kay, Caroline G. McPhee, Gayatri Mukherjee, Deanna J. Lamont, Steven C. Almo |
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| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 193:2135-2146 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1400997 |
| Popis: | Self-reactive T cells must escape thymic negative selection to mediate pathogenic autoimmunity. In the NOD mouse model of autoimmune diabetes, several β cell–cytotoxic CD8 T cell populations are known, with the most aggressive of these represented by AI4, a T cell clone with promiscuous Ag-recognition characteristics. We identified a long-elusive β cell–specific ligand for AI4 as an unusually short H-2Db–binding 7-mer peptide lacking a C-terminal anchor residue and derived from the insulin A chain (InsA14–20). Crystallography reveals that compensatory mechanisms permit peptides lacking a C-terminal anchor to bind sufficiently to the MHC to enable destructive T cell responses, yet allow cognate T cells to avoid negative selection. InsA14–20 shares two solvent-exposed residues with previously identified AI4 ligands, providing a structural explanation for AI4’s promiscuity. Detection of AI4-like T cells, using mimotopes of InsA14–20 with improved H-2Db–binding characteristics, establishes the AI4-like T cell population as a consistent feature of the islet infiltrates of NOD mice. Our work establishes undersized peptides as previously unrecognized targets of autoreactive CD8 T cells and presents a strategy for their further exploration as Ags in autoimmune disease. |
| Databáze: | OpenAIRE |
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