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 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.

Modulation of γδ T‐cell activation by neutrophil elastase

“…Furthermore, γδ T cells not only display differences at the CD3 conformation, but also show differences in the intracellular signalling downstream of the TCR. Hence, triggering conformational changes in CD3 in the TCR‐ γδ led to enhanced signalling events . More interesting, Dopfer et al .…”

“…These results suggest that different stimuli induce diverse activation states of γδ T cells, which allow them to respond differentially to extracellular factors. In this regard, it has been reported that stimulation by anti‐CD3 antibodies triggers conformational changes in the human V γ 9V δ 2 TCR . Moreover, different anti‐CD3 antibodies, such as UCHT1 and OKT3, promote differential responses on γδ T cells, UCHT1 antibodies being more potent to prompt CD3 conformational changes than OKT3 .…”

“…In this regard, it has been reported that stimulation by anti‐CD3 antibodies triggers conformational changes in the human V γ 9V δ 2 TCR . Moreover, different anti‐CD3 antibodies, such as UCHT1 and OKT3, promote differential responses on γδ T cells, UCHT1 antibodies being more potent to prompt CD3 conformational changes than OKT3 . Furthermore, γδ T cells not only display differences at the CD3 conformation, but also show differences in the intracellular signalling downstream of the TCR.…”

“…45 Moreover, different anti-CD3 antibodies, such as UCHT1 and OKT3, promote differential responses on cd T cells, UCHT1 antibodies being more potent to prompt CD3 conformational changes than OKT3. 45 Furthermore, cd T cells not only display differences at the CD3 conformation, but also show differences in the intracellular signalling downstream of the TCR. Hence, triggering conformational changes in CD3 in the TCR-cd led to enhanced signalling events.…”

In memoriam: Paul Fisch (1959–2018) our dear friend, pioneer of γδ T cell research, esteemed scientist, and dedicated clinician

“…Beyond his early work, Paul continued to make crucial contributions as a sharp, fair reviewer and critical discussion partner for these companies. Naturally, Paul's research also continued in this vein, with recent papers on enhancement of tumour cell killing via manipulation of the cd T cell antigen receptor 12,13 and analysis of cd T cells infiltrating triple-negative breast cancers. 14 Paul not only thought about science, he also loved performing experiments!…”