Anti-CD3 Fab Fragments Enhance Tumor Killing by Human ?? T Cells Independent of Nck Recruitment to the ?? T Cell Antigen Receptor.

ABSTRACT: T lymphocytes expressing the ?? T cell receptor (?? TCR) can recognize antigens expressed by tumor cells and subsequently kill these cells. ?? T cells are indeed used in cancer immunotherapy clinical trials. The anti-CD3? antibody UCHT1 enhanced the in vitro tumor killing activity of human ?? T cells by an unknown molecular mechanism. Here, we demonstrate that Fab fragments of UCHT1, which only bind monovalently to the ?? TCR, also enhanced tumor killing by expanded human V?9V?2 ?? T cells or pan-?? T cells of the peripheral blood. The Fab fragments induced Nck recruitment to the ?? TCR, suggesting that they stabilized the ?? TCR in an active CD3? conformation. However, blocking the Nck-CD3? interaction in ?? T cells using the small molecule inhibitor AX-024 neither reduced the ?? T cells' natural nor the Fab-enhanced tumor killing activity. Likewise, Nck recruitment to CD3? was not required for intracellular signaling, CD69 and CD25 up-regulation, or cytokine secretion by ?? T cells. Thus, the Nck-CD3? interaction seems to be dispensable in ?? T cells.

SUBMITTER: Juraske C 

PROVIDER: S-EPMC6046647 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature