Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo

J Immunol. 2014 Mar 1;192(5):2042-53. doi: 10.4049/jimmunol.1203414. Epub 2014 Jan 27.


On TCR ligation, the adaptor Nck is recruited through its src homology 3.1 domain to a proline-rich sequence (PRS) in CD3ε. We have studied the relevance of this interaction for T cell activation in vitro and in vivo by targeting the interaction sites in both partners. The first approach consisted of studying a knockin (KI) mouse line (KI-PRS) bearing a conservative mutation in the PRS that makes the TCR incompetent to recruit Nck. This deficiency prevents T cell activation by Ag in vitro and inhibited very early TCR signaling events including the tyrosine phosphorylation of CD3ζ. Most important, KI-PRS mice are partly protected against the development of neurological symptoms in an experimental autoimmune encephalitis model, and show a deficient antitumoral response after vaccination. The second approach consisted of using a high-affinity peptide that specifically binds the src homology 3.1 domain and prevents the interaction of Nck with CD3ε. This peptide inhibits T cell proliferation in vitro and in vivo. These data suggest that Nck recruitment to the TCR is fundamental to mount an efficient T cell response in vivo, and that the Nck-CD3ε interaction may represent a target for pharmacological modulation of the immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Animals
  • Antigens / genetics
  • Antigens / immunology
  • CD3 Complex / genetics
  • CD3 Complex / immunology*
  • Cell Proliferation
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation / physiology*
  • Mice
  • Mice, Mutant Strains
  • Oncogene Proteins / genetics
  • Oncogene Proteins / immunology*
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / physiology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*


  • Adaptor Proteins, Signal Transducing
  • Antigens
  • CD3 Complex
  • CD3E protein, human
  • Cd3e protein, mouse
  • Nck protein
  • Oncogene Proteins
  • Receptors, Antigen, T-Cell