The CD3 Conformational Change in the γδ T Cell Receptor Is Not Triggered by Antigens but Can Be Enforced to Enhance Tumor Killing

Activation of the T cell receptor (TCR) by antigen is the key step in adaptive immunity. In the alpha beta TCR, antigen induces a conformational change at the CD3 subunits (CD3 CC) that is absolutely required for alpha beta TCR activation. Here, we demonstrate that the CD3 CC is not induced by antigen stimulation of the mouse G8 or the human V gamma 9V delta 2 gamma delta TCR. We find that there is a fundamental difference between the activation mechanisms of the alpha beta TCR and gamma delta TCR that map to the constant regions of the TCR alpha beta/gamma delta heterodimers. Enforced induction of CD3 CC with a less commonly used monoclonal anti-CD3 promoted proximal gamma delta TCR signaling but inhibited cytokine secretion. Utilizing this knowledge, we could dramatically improve in vitro tumor cell lysis by activated human gamma delta T cells. Thus, manipulation of the CD3 CC might be exploited to improve clinical gamma delta T cell-based immunotherapies.