Cooperative binding of T cell receptor and CD4 to peptide-MHC enhances antigen sensitivity

• Type of Material: Article
• Authors: Muaz N Rushdi, Georgia Institute of Technology; Victor Pan, Georgia Institute of Technology; Kaitao Li, Georgia Institute of Technology; Hyun-Kyu Choi, Georgia Institute of Technology; Stefano Travaglino, Georgia Institute of Technology; Jinsung Hong, Georgia Institute of Technology; Fletcher Griffitts, Georgia Institute of Technology; Pragati Agnihotri, University of Maryland, Rockville; Roy A Mariuzza, University of Maryland, Rockville; Yonggang Ke, Emory University; Cheng Zhu, Emory University
• Language: English
• Date: 2022-11-17
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-34587-w
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 13
• Issue: 1
• Start Page: 7055
• End Page: 7055
• Grant/Funding Information: This work was supported by NIH grants R21AI135753 (to Y.K and C.Z.), R01GM124489, U01CA214354, and U01CA250040 (to C.Z.), R01AI129893 (to R.A.M.), and National Research Foundation grants of South Korea 2021R1A6A3A03038382 (to H.-K.C.).
• Keywords: CATCH BONDS; COMPLEX; Multidisciplinary Sciences; CONCURRENT BINDING; TCR; ACCUMULATION; LIGAND; ADHESION; Science & Technology; KINETICS; CRYSTAL-STRUCTURE; SURFACES; Science & Technology - Other Topics
• Research Categories: Engineering, Biomedical

Abstract

Antigen recognition by the T cell receptor (TCR) of CD4+ T cells can be greatly enhanced by the coreceptor CD4. Yet, understanding of the molecular mechanism is hindered by the ultra-low affinity of CD4 binding to class-II peptide-major histocompatibility complexes (pMHC). Here we show, using two-dimensional (2D) mechanical-based assays, that the affinity of CD4–pMHC interaction is 3-4 logs lower than that of cognate TCR–pMHC interactions, and it is more susceptible to increased dissociation by forces (slip bond). In contrast, CD4 binds TCR-pre-bound pMHC at 3-6 logs higher affinity, forming TCR–pMHC–CD4 tri-molecular bonds that are prolonged by force (catch bond), and modulated by protein mobility on the cell membrane, indicating profound TCR-CD4 cooperativity. Consistent with a tri-crystal structure, using DNA origami as a molecular ruler to titrate spacing between TCR and CD4 we show that 7-nm proximity optimizes TCR–pMHC–CD4 tri-molecular bond formation with pMHC. Our results thus provide deep mechanistic insight into CD4 enhancement of TCR antigen recognition.