Abstract
T lymphocytes expressing the γδ T cell receptor (γδ TCR) can recognize antigens expressed by tumor cells and subsequently kill these cells. γδ T cells are indeed used in cancer immunotherapy clinical trials. The anti-CD3ε antibody UCHT1 enhanced the in vitro tumor killing activity of human γδ T cells by an unknown molecular mechanism. Here, we demonstrate that Fab fragments of UCHT1, which only bind monovalently to the γδ TCR, also enhanced tumor killing by expanded human Vγ9Vδ2 γδ T cells or pan-γδ T cells of the peripheral blood. The Fab fragments induced Nck recruitment to the γδ TCR, suggesting that they stabilized the γδ TCR in an active CD3ε conformation. However, blocking the Nck-CD3ε interaction in γδ T cells using the small molecule inhibitor AX-024 neither reduced the γδ T cells’ natural nor the Fab-enhanced tumor killing activity. Likewise, Nck recruitment to CD3ε was not required for intracellular signaling, CD69 and CD25 up-regulation, or cytokine secretion by γδ T cells. Thus, the Nck-CD3ε interaction seems to be dispensable in γδ T cells.
Highlights
T cells are part of the adaptive immune system and can be divided into αβ and γδ T cells, depending on the T cell antigen receptor (TCR) they express
We concluded that AX-024 did not diminish tumor killing for the zoledronate-expanded γδ T cells. These findings indicate that Nck recruitment to the γδ T cell receptor (γδ TCR) is dispensable for the cytotoxic activity of γδ T cells stimulated by tumor cells
Since γδ T cells are independent of antigen presentation by MHC class I and of the presence of mutated epitopes, they are ideal effectors against tumors with low mutation loads
Summary
T cells are part of the adaptive immune system and can be divided into αβ and γδ T cells, depending on the T cell antigen receptor (TCR) they express. Γδ T cells recognize cell surface molecules that are differentially expressed on transformed solid tumors or lymphomas and leukemias [7, 15]. An enhanced production of phosphoantigens in transformed cells can be further increased by therapeutically administered nitrogen-containing bisphosphonates, such as zoledronate, which inhibit the farnesyl pyrophosphate synthase of the isoprenoid pathway [16, 17]. While sustained stimulation of Vγ9Vδ2 γδ T cells by phosphoantigens or nitrogen-containing bisphosphonates often leads to their exhaustion, bispecific antibodies provide a newly tool to target γδ T cells to antigens expressed by tumor cells and enhanced their cytotoxic activity [19, 21,22,23]. The exact molecular mechanism leading to phosphoantigen recognition is a matter of debate [24, 25], this recognition is clearly mediated by cognate interaction with the Vγ9Vδ2 TCR
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
