Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo.
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.
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain;
Aldo
A
Borroto
Irene
I
Arellano
Raquel
R
Blanco
Manuel
M
Fuentes
Alberto
A
Orfao
Elaine P
EP
Dopfer
Marek
M
Prouza
Miloslav
M
Suchànek
Wolfgang W
WW
Schamel
Balbino
B
Alarcón
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D015513:Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D017252:CD3 Complex; C115335:CD3E protein, human; C485468:Cd3e protein, mouse; C078332:Nck protein; D015513:Oncogene Proteins; D011948:Receptors, Antigen, T-Cell