| First Author | Stepanek O | Year | 2014 |
| Journal | Cell | Volume | 159 |
| Issue | 2 | Pages | 333-45 |
| PubMed ID | 25284152 | Mgi Jnum | J:217551 |
| Mgi Id | MGI:5614527 | Doi | 10.1016/j.cell.2014.08.042 |
| Citation | Stepanek O, et al. (2014) Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell 159(2):333-45 |
| abstractText | In the thymus, high-affinity, self-reactive thymocytes are eliminated from the pool of developing T cells, generating central tolerance. Here, we investigate how developing T cells measure self-antigen affinity. We show that very few CD4 or CD8 coreceptor molecules are coupled with the signal-initiating kinase, Lck. To initiate signaling, an antigen-engaged T cell receptor (TCR) scans multiple coreceptor molecules to find one that is coupled to Lck; this is the first and rate-limiting step in a kinetic proofreading chain of events that eventually leads to TCR triggering and negative selection. MHCII-restricted TCRs require a shorter antigen dwell time (0.2 s) to initiate negative selection compared to MHCI-restricted TCRs (0.9 s) because more CD4 coreceptors are Lck-loaded compared to CD8. We generated a model (Lck come&stay/signal duration) that accurately predicts the observed differences in antigen dwell-time thresholds used by MHCI- and MHCII-restricted thymocytes to initiate negative selection and generate self-tolerance. |
