Cooperative binding of TCR and CD4 to pMHC enhances TCR sensitivity

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 that 7-nm proximity optimizes trimolecular bond formation with pMHC. Our results reveal how CD4 augments TCR antigen recognition.

[1]  R. Ahmed,et al.  PD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition , 2021, Nature Communications.

[2]  R. Nussinov,et al.  Peptide-MHC Binding Reveals Conserved Allosteric Sites in MHC Class I- and Class II-Restricted T Cell Receptors (TCRs). , 2020, Journal of molecular biology.

[3]  Michael Loran Dustin,et al.  Coreceptors and TCR Signaling – the Strong and the Weak of It , 2020, Frontiers in Cell and Developmental Biology.

[4]  J. Lou,et al.  Mechanosensing through immunoreceptors , 2019, Nature Immunology.

[5]  Jia-huai Wang,et al.  Structural basis of assembly of the human T cell receptor–CD3 complex , 2019, Nature.

[6]  A. Rubinstein.  Signaling , 2019, Hardness of Approximation Between P and NP.

[7]  M. Cebecauer,et al.  Dual Role of CD4 in Peripheral T Lymphocytes , 2019, Front. Immunol..

[8]  K. Salaita,et al.  A TCR mechanotransduction signaling loop induces negative selection in the thymus , 2018, Nature Immunology.

[9]  Ruth Nussinov,et al.  Peptide–MHC (pMHC) binding to a human antiviral T cell receptor induces long-range allosteric communication between pMHC- and CD3-binding sites , 2018, The Journal of Biological Chemistry.

[10]  Mark S. Lee,et al.  Reciprocal TCR-CD3 and CD4 Engagement of a Nucleating pMHCII Stabilizes a Functional Receptor Macrocomplex , 2018, Cell reports.

[11]  A. Weiss,et al.  TCR Signaling: Mechanisms of Initiation and Propagation. , 2017, Trends in biochemical sciences.

[12]  Peter Schuck,et al.  An allosteric site in the T-cell receptor Cβ domain plays a critical signalling role , 2017, Nature Communications.

[13]  Paul D. Dunne,et al.  Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions , 2016, Proceedings of the National Academy of Sciences.

[14]  P. Allen,et al.  Force-Regulated In Situ TCR–Peptide-Bound MHC Class II Kinetics Determine Functions of CD4+ T Cells , 2015, The Journal of Immunology.

[15]  V. Vasioukhin.  Faculty Opinions recommendation of Cell adhesion. The minimal cadherin-catenin complex binds to actin filaments under force. , 2014 .

[16]  R. Zamoyska,et al.  Ligand engaged TCR is triggered by Lck not associated with CD8 coreceptor , 2014, Nature Communications.

[17]  A. Chakraborty,et al.  Coreceptor Scanning by the T Cell Receptor Provides a Mechanism for T Cell Tolerance , 2014, Cell.

[18]  Cheng Zhu,et al.  Accumulation of Dynamic Catch Bonds between TCR and Agonist Peptide-MHC Triggers T Cell Signaling , 2014, Cell.

[19]  S. Rosenberg,et al.  2D TCR–pMHC–CD8 kinetics determines T‐cell responses in a self‐antigen‐specific TCR system , 2014, European journal of immunology.

[20]  R. Mariuzza,et al.  Crystal structure of a complete ternary complex of T-cell receptor, peptide–MHC, and CD4 , 2012, Proceedings of the National Academy of Sciences.

[21]  Qian Wang,et al.  Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4–HLA-DR1 complex , 2011, Proceedings of the National Academy of Sciences.

[22]  B. Evavold,et al.  Two-stage cooperative T cell receptor-peptide major histocompatibility complex-CD8 trimolecular interactions amplify antigen discrimination. , 2011, Immunity.

[23]  Cheng Zhu,et al.  The kinetics of two dimensional TCR and pMHC interactions determine T cell responsiveness , 2010, Nature.

[24]  Evan W. Newell,et al.  TCR–peptide–MHC interactions in situ show accelerated kinetics and increased affinity , 2010, Nature.

[25]  V. Zarnitsyna,et al.  Measuring Receptor–Ligand Binding Kinetics on Cell Surfaces: From Adhesion Frequency to Thermal Fluctuation Methods , 2008, Cellular and molecular bioengineering.

[26]  Wei Chen,et al.  Monitoring receptor-ligand interactions between surfaces by thermal fluctuations. , 2008, Biophysical journal.

[27]  Cheng Zhu,et al.  Kinetics of MHC-CD8 Interaction at the T Cell Membrane1 , 2007, Journal of Immunology.

[28]  P. Rothemund.  Folding DNA to create nanoscale shapes and patterns , 2006, Nature.

[29]  P. Allen,et al.  An antagonist peptide mediates positive selection and CD4 lineage commitment of MHC class II–restricted T cells in the absence of CD4 , 2005, The Journal of experimental medicine.

[30]  Cheng Zhu,et al.  Mechanical switching and coupling between two dissociation pathways in a P-selectin adhesion bond. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Arup K Chakraborty,et al.  CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse , 2004, Nature Immunology.

[32]  Cheng Zhu,et al.  Direct observation of catch bonds involving cell-adhesion molecules , 2003, Nature.

[33]  P. Selvaraj,et al.  Quantifying the Impact of Membrane Microtopology on Effective Two-dimensional Affinity* 210 , 2001, The Journal of Biological Chemistry.

[34]  Ellis L. Reinherz,et al.  T Cell Receptor Binding to a pMHCII Ligand Is Kinetically Distinct from and Independent of CD4* , 2001, The Journal of Biological Chemistry.

[35]  C. Zhu,et al.  Concurrent and independent binding of Fcgamma receptors IIa and IIIb to surface-bound IgG. , 2000, Biophysical journal.

[36]  C. Zhu,et al.  Concurrent binding to multiple ligands: kinetic rates of CD16b for membrane-bound IgG1 and IgG2. , 2000, Biophysical journal.

[37]  C. Zhu,et al.  Modeling concurrent binding of multiple molecular species in cell adhesion. , 2000, Biophysical journal.

[38]  C. Zhu,et al.  Measuring two-dimensional receptor-ligand binding kinetics by micropipette. , 1998, Biophysical journal.

[39]  P. Marrack,et al.  Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes. , 1998, Immunity.

[40]  Margot Thome,et al.  The p56lck SH2 domain mediates recruitment of CD8/p56lck to the activated T cell receptor/CD3/ζ complex , 1996, European journal of immunology.

[41]  김정기,et al.  Propagation , 1994, Encyclopedia of Evolutionary Psychological Science.

[42]  O. Acuto,et al.  p56lck interacts via its src homology 2 domain with the ZAP-70 kinase , 1994, The Journal of experimental medicine.

[43]  D. Littman,et al.  A kinase-independent function of Lck in potentiating antigen-specific T cell activation , 1993, Cell.

[44]  P. Anderson,et al.  Biochemical identification of a direct physical interaction between the CD4: p56lck and Ti(TcR)/CD3 complexes , 1991, European journal of immunology.

[45]  P. Parham,et al.  Cell-cell adhesion mediated by CD8 and MHC class I molecules , 1988, Nature.

[46]  C. Rudd,et al.  The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[47]  J. Strominger,et al.  Interaction between CD4 and class II MHC molecules mediates cell adhesion , 1987, Nature.

[48]  M. Reivich,et al.  ACTIVATION , 1980, The Social Value of Zoos.

[49]  G. I. Bell.  Models for the specific adhesion of cells to cells. , 1978, Science.

[50]  M. Nishimura,et al.  Structural basis for the recognition of mutant self by a tumor-specific, MHC class II–restricted T cell receptor , 2007, Nature Immunology.

[51]  C. Rudd.  CD4, CD8 and the TCR-CD3 complex: a novel class of protein-tyrosine kinase receptor. , 1990, Immunology today.