The CD3 conformational change in the ?? T Cell receptor is not triggered by antigens but can be enforced to enhance tumor killing
21.05.2014
Dopfer EP, Hartl FA, Oberg HH, Siegers GM, Yousefi OS, Kock S, Fiala GJ, Garcillán B, Sandstrom A, Alarcón B, Regueiro JR, Kabelitz D, Adams EJ, Minguet S, Wesch D, Fisch P, Schamel WW.
Cell Rep. 2014;7(5):1704-15
In this BIOSS publication we analyse the molecular requirements for the activation of the ?? T-cell receptor (??TCR) in human and in mouse T cells. We compare the ??TCR with the more commonly studied ??TCR and found that there is a fundamental difference between ??TCR and TCR activation mechanisms. In the ??TCR, antigen induces a conformational change at the the CD3 subunit (CD3 CC) that is absolutely required for ??TCR activation. In this paper, we demonstrate that the CD3 CC is not induced by antigenic stimulation of the ??TCR. The difference between the activation mechanisms of the ??TCR and ??TCR mapped to the constant regions of the TCR??/?? heterodimers. Enforced induction of CD3 CC, by using the monoclonal anti- CD3 antibody UCHT1, promoted proximal ??TCR signaling, but inhibited cytokine secretion. This was in contrast to the monoclonal antibody OKT3, which did not induce the CD3 CC. Utilizing this knowledge, we could dramatically improve in vitro tumor cell lysis by activated human ?? T cells. Hence, this paper improved knowledge on the signal transduction mechanism of the TCRs. We further conclude that manipulation of the CD3 CC could be exploited in the future to improve clinical ?? T cell-based immunotherapies.
