The CD3 conformational change in the γδ T cell receptor is not triggered by antigens but can be enforced to enhance tumor killing

Cell Rep. 2014 Jun 12;7(5):1704-1715. doi: 10.1016/j.celrep.2014.04.049. Epub 2014 May 22.


Activation of the T cell receptor (TCR) by antigen is the key step in adaptive immunity. In the αβTCR, antigen induces a conformational change at the CD3 subunits (CD3 CC) that is absolutely required for αβTCR activation. Here, we demonstrate that the CD3 CC is not induced by antigen stimulation of the mouse G8 or the human Vγ9Vδ2 γδTCR. We find that there is a fundamental difference between the activation mechanisms of the αβTCR and γδTCR that map to the constant regions of the TCRαβ/γδ heterodimers. Enforced induction of CD3 CC with a less commonly used monoclonal anti-CD3 promoted proximal γδTCR signaling but inhibited cytokine secretion. Utilizing this knowledge, we could dramatically improve in vitro tumor cell lysis by activated human γδ T cells. Thus, manipulation of the CD3 CC might be exploited to improve clinical γδ T cell-based immunotherapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / chemistry*
  • CD3 Complex / immunology
  • Cell Line
  • Cytotoxicity, Immunologic*
  • Humans
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • Protein Conformation
  • Receptor-CD3 Complex, Antigen, T-Cell / chemistry
  • Receptor-CD3 Complex, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / chemistry*
  • Receptors, Antigen, T-Cell, gamma-delta / immunology
  • T-Lymphocytes / immunology


  • CD3 Complex
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Receptors, Antigen, T-Cell, gamma-delta