| First Author | Lynch JN | Year | 2013 |
| Journal | Mol Immunol | Volume | 53 |
| Issue | 3 | Pages | 283-94 |
| PubMed ID | 22982754 | Mgi Jnum | J:188284 |
| Mgi Id | MGI:5440126 | Doi | 10.1016/j.molimm.2012.08.020 |
| Citation | Lynch JN, et al. (2013) Subtle changes in TCRalpha CDR1 profoundly increase the sensitivity of CD4 T cells. Mol Immunol 53(3):283-94 |
| abstractText | Changes in the peptide and MHC molecules have been extensively examined for how they alter T cell activation, but many fewer studies have examined the TCR. Structural studies of how TCR differences alter T cell specificity have focused on broad variation in the CDR3 loops. However, changes in the CDR1 and 2 loops can also alter TCR recognition of pMHC. In this study we focus on two mutations in the CDR1alpha loop of the TCR that increased the affinity of a TCR for agonist Hb(64-76)/I-E(k) by increasing the on-rate of the reaction. These same mutations also conferred broader recognition of altered peptide ligands. TCR transgenic mice expressing the CDR1alpha mutations had altered thymic selection, as most of the T cells were negatively selected compared to T cells expressing the wildtype TCR. The few T cells that escaped negative selection and were found in the periphery were rendered anergic, thereby avoiding autoimmunity. T cells with the CDR1alpha mutations were completely deleted in the presence of Hb(64-76) as an endogenous peptide. Interestingly, the wildtype T cells were not eliminated, identifying a threshold affinity for negative selection where a 3-fold increase in affinity is the difference between incomplete and complete deletion. Overall, these studies highlight how small changes in the TCR can increase the affinity of TCR:pMHC but with the consequences of skewing selection and producing an unresponsive T cell. |
