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; Cheng Zhu

doi:10.1038/s41467-022-34587-w

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

Nat Commun. 2022 Nov 17;13(1):7055. doi: 10.1038/s41467-022-34587-w.

Authors

Muaz Nik Rushdi^#^{1

2

3}, Victor Pan^#^{1

2

4}, Kaitao Li^#^{1

2}, Hyun-Kyu Choi^#^{1

2}, Stefano Travaglino^{1

2}, Jinsung Hong^{1

2

5}, Fletcher Griffitts^{2

6}, Pragati Agnihotri^{7

8

9}, Roy A Mariuzza^{7

8}, Yonggang Ke^{10

11}, Cheng Zhu^{12

13

14}

Affiliations

¹ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
² Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
³ Medtronic CO., Minneapolis, MN, USA.
⁴ Intellia Therapeutics, Cambridge, MA, USA.
⁵ Food and Drug Administration, Silver Spring, MD, USA.
⁶ Georgia W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
⁷ W. M. Keck Laboratory for Structural Biology, Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, USA.
⁸ Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA.
⁹ Advanced Bioscience Laboratories, Rockville, MD, USA.
¹⁰ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. yonggang.ke@emory.edu.
¹¹ Medical Scientist Training Program, Emory University School of Medicine, Atlanta, GA, USA. yonggang.ke@emory.edu.
¹² Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. cheng.zhu@bme.gatech.edu.
¹³ Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA. cheng.zhu@bme.gatech.edu.
¹⁴ Georgia W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. cheng.zhu@bme.gatech.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Antigens*
Histocompatibility Antigens
Major Histocompatibility Complex
Peptides / chemistry
Receptors, Antigen, T-Cell* / metabolism

Substances

Receptors, Antigen, T-Cell
Antigens
Histocompatibility Antigens
Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding