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

Abstract

Activation of the Tcell 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 invitro tumor cell lysis by activated human γδ Tcells. Thus, manipulation of the CD3 CC might be exploited to improve clinical γδ Tcell-based immunotherapies.