Title |
Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding
|
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Published in |
Cell, July 2018
|
DOI | 10.1016/j.cell.2018.06.017 |
Pubmed ID | |
Authors |
Leah V. Sibener, Ricardo A. Fernandes, Elizabeth M. Kolawole, Catherine B. Carbone, Fan Liu, Darren McAffee, Michael E. Birnbaum, Xinbo Yang, Laura F. Su, Wong Yu, Shen Dong, Marvin H. Gee, Kevin M. Jude, Mark M. Davis, Jay T. Groves, William A. Goddard, James R. Heath, Brian D. Evavold, Ronald D. Vale, K. Christopher Garcia |
Abstract |
TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR. Single-molecule force measurements demonstrated the emergence of catch bonds in the activating TCR-pMHC interactions, correlating with exclusion of CD45 from the TCR-APC contact site. Molecular dynamics simulations of TCR-pMHC disengagement distinguished agonist from non-agonist ligands based on the acquisition of catch bonds within the TCR-pMHC interface. The isolation of catch bonds as a parameter mediating the coupling of TCR binding and signaling has important implications for TCR and antigen engineering for immunotherapy. |
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Country | Count | As % |
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United States | 26 | 33% |
United Kingdom | 8 | 10% |
France | 4 | 5% |
Germany | 3 | 4% |
Austria | 2 | 3% |
Singapore | 1 | 1% |
Sweden | 1 | 1% |
South Africa | 1 | 1% |
Iraq | 1 | 1% |
Other | 7 | 9% |
Unknown | 25 | 32% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 46 | 58% |
Scientists | 29 | 37% |
Practitioners (doctors, other healthcare professionals) | 3 | 4% |
Science communicators (journalists, bloggers, editors) | 1 | 1% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 433 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 122 | 28% |
Researcher | 73 | 17% |
Other | 33 | 8% |
Student > Bachelor | 31 | 7% |
Student > Doctoral Student | 29 | 7% |
Other | 61 | 14% |
Unknown | 84 | 19% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 99 | 23% |
Immunology and Microbiology | 91 | 21% |
Agricultural and Biological Sciences | 51 | 12% |
Chemistry | 28 | 6% |
Engineering | 22 | 5% |
Other | 47 | 11% |
Unknown | 95 | 22% |