TY - JOUR T1 - Cooperative binding of TCR and CD4 to pMHC enhances TCR sensitivity JF - bioRxiv DO - 10.1101/2021.11.22.469547 SP - 2021.11.22.469547 AU - Muaz Nik Rushdi AU - Victor Pan AU - Kaitao Li AU - Stefano Travaglino AU - Hyun-Kyu Choi AU - Jinsung Hong AU - Fletcher Griffitts AU - Pragati Agnihotri AU - Roy A. Mariuzza AU - Yonggang Ke AU - Cheng Zhu Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/11/22/2021.11.22.469547.abstract N2 - Antigen recognition of CD4+ T cells by the T cell receptor (TCR) can be greatly enhanced by the coreceptor CD41–7. Yet, understanding of the molecular mechanism is hindered by the ultra-low affinity of CD4 binding to class-II peptide-major histocompatibility complexes (pMHC)1,7–10. Using two-dimensional (2D) mechanical-based assays, we determined a CD4–pMHC interaction to have 3-4 logs lower affinity than cognate TCR–pMHC interactions8, and to be susceptible to increased dissociation by forces (slip bond)5,8,11. In contrast, CD4 binds TCR-prebound pMHC at 5-6 logs higher affinity, forming TCR–pMHC–CD4 trimolecular bonds that are prolonged by force (catch bond)5,8,11 and modulated by protein mobility on the cell membrane, indicating profound TCR–CD4 cooperativity. Consistent with a tri-crystal structure12, using DNA origami as a molecular ruler to titrate spacing between TCR and CD4 indicates 7-nm proximity enables optimal trimolecular bond formation with pMHC. Our results reveal how CD4 augments TCR antigen recognition.Competing Interest StatementThe authors have declared no competing interest. ER -