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

Muaz Nik Rushdi, Victor Pan, Kaitao Li, Hyun-Kyu Choi, Stefano Travaglino, Jinsung Hong, Fletcher Griffitts, Pragati Agnihotri, Roy A. Mariuzza, Yonggang Ke () and Cheng Zhu ()
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Muaz Nik Rushdi: Georgia Institute of Technology and Emory University
Victor Pan: Georgia Institute of Technology and Emory University
Kaitao Li: Georgia Institute of Technology and Emory University
Hyun-Kyu Choi: Georgia Institute of Technology and Emory University
Stefano Travaglino: Georgia Institute of Technology and Emory University
Jinsung Hong: Georgia Institute of Technology and Emory University
Fletcher Griffitts: Georgia Institute of Technology
Pragati Agnihotri: University of Maryland
Roy A. Mariuzza: University of Maryland
Yonggang Ke: Georgia Institute of Technology and Emory University
Cheng Zhu: Georgia Institute of Technology and Emory University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34587-w

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