| First Author | Blanco R | Year | 2014 |
| Journal | Sci Signal | Volume | 7 |
| Issue | 354 | Pages | ra115 |
| PubMed ID | 25468995 | Mgi Jnum | J:259023 |
| Mgi Id | MGI:6140511 | Doi | 10.1126/scisignal.2005650 |
| Citation | Blanco R, et al. (2014) Conformational changes in the T cell receptor differentially determine T cell subset development in mice. Sci Signal 7(354):ra115 |
| abstractText | In the thymus, immature T cells differentiate from common precursors to become T cells expressing either the alphabeta or gammadelta T cell receptor (TCR) complex. The CD3epsilon subunit of the TCR complex is thought to transduce ligand-induced conformational changes in the TCR by recruiting the cytosolic adaptor protein Nck. To investigate the role of conformational changes in the TCR in T cell development, we generated mice with a germline mutation (C80G) in the extracellular domain of CD3epsilon, which prevents the outside-in transmission of conformational changes in the TCR. The development of alphabeta T cells in the C80G mice was blocked at an early stage that depends on signaling by a precursor form of the TCR. In contrast, the C80G mutation did not impair the development of some subsets of gammadelta T cells, including Vgamma1.1(+) cells; however, development of other gammadelta T cell subsets was blocked. A similar phenotype was observed in mice with a mutation in the cytoplasmic proline-rich sequence (PRS) of CD3epsilon, the binding site for Nck. In a genetic complementation test, the PRS CD3epsilon mutant failed to rescue the wild-type phenotype when expressed in heterozygosity with the C80G mutant. These data suggest that Nck may function as an effector of TCR conformational changes during T cell development. Additional experiments showed differential effects of the C80G mutation on the activation of TCR-dependent signaling pathways, which suggests that there are pathways that are either dependent on or independent of the transmission of conformational change in the receptor. |
