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

Author

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  • Muaz Nik Rushdi

    (Georgia Institute of Technology and Emory University
    Georgia Institute of Technology
    Medtronic CO.)

  • Victor Pan

    (Georgia Institute of Technology and Emory University
    Georgia Institute of Technology
    Intellia Therapeutics)

  • Kaitao Li

    (Georgia Institute of Technology and Emory University
    Georgia Institute of Technology)

  • Hyun-Kyu Choi

    (Georgia Institute of Technology and Emory University
    Georgia Institute of Technology)

  • Stefano Travaglino

    (Georgia Institute of Technology and Emory University
    Georgia Institute of Technology)

  • Jinsung Hong

    (Georgia Institute of Technology and Emory University
    Georgia Institute of Technology
    Food and Drug Administration)

  • Fletcher Griffitts

    (Georgia Institute of Technology
    Georgia Institute of Technology)

  • Pragati Agnihotri

    (University of Maryland
    University of Maryland
    Advanced Bioscience Laboratories)

  • Roy A. Mariuzza

    (University of Maryland
    University of Maryland)

  • Yonggang Ke

    (Georgia Institute of Technology and Emory University
    Emory University School of Medicine)

  • Cheng Zhu

    (Georgia Institute of Technology and Emory University
    Georgia Institute of Technology
    Georgia Institute of Technology)

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.

Suggested Citation

  • Muaz Nik Rushdi & Victor Pan & Kaitao Li & Hyun-Kyu Choi & Stefano Travaglino & Jinsung Hong & Fletcher Griffitts & Pragati Agnihotri & Roy A. Mariuzza & Yonggang Ke & Cheng Zhu, 2022. "Cooperative binding of T cell receptor and CD4 to peptide-MHC enhances antigen sensitivity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34587-w
    DOI: 10.1038/s41467-022-34587-w
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    References listed on IDEAS

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    Cited by:

    1. Hyun-Kyu Choi & Peiwen Cong & Chenghao Ge & Aswin Natarajan & Baoyu Liu & Yong Zhang & Kaitao Li & Muaz Nik Rushdi & Wei Chen & Jizhong Lou & Michelle Krogsgaard & Cheng Zhu, 2023. "Catch bond models may explain how force amplifies TCR signaling and antigen discrimination," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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