Functional avidity of T cells Engineered with a defined Gamma delta TCR (TEGs) is dictated by NKG2D and the affinity of individual γ9δ2TCRs
Anna Vyborova2*, Cordula Gründer2, Dennis Beringer2, Trudy Straetemans2, Zsolt Sebestyen2 and Jürgen Kuball1,2
1Department of Hematology, 2Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
T cells engineered to express a defined gamma delta TCR (TEGs) are currently explored for clinical application (1), and we have previously demonstrated that diversity in CDR3 region of the γ9δ2 TCR itself determines functional avidity of TEGs (2). In order to better molecular characterize orchestration of different molecules involved in the functional avidity of TEGs we generated soluble γ9δ2 TCRs based on γδTCR sequences from T cell clones with unequal reactivity. In line with our previous findings, soluble γδ TCRs showed differential blocking potential in T cell activation assays.
NK-receptors have the potential to further shape the effector functions of γ9δ2 T cells, however the details of their interplay with diverse γ9δ2 TCRs remain poorly understood. We addressed the role of the activating NK-receptor NKG2D in the context of different affinity TEGs. By co-expressing low- and high-affinity γ9δ2 TCRs in CD4+ αβT cells with NKG2D, we found that NKG2D acts in a co-stimulatory fashion, being unable to trigger T cell response when co-expressed with a non-functional γ9δ2 TCR. Contribution of NKG2D to T cell function is substantial when NKG2D is co-expressed with a “weak” γ9δ2 TCR or when expression of putative γ9δ2 TCR ligands on a target cell is low. In contrast, little to no NKG2D contribution is observed in case of the high avidity of the TCR-mediated interaction. These new molecular insights might allow a better design of T cells engineered to express a defined gamma delta TCR.
Straetemans T et al. Untouched GMP-Ready Purified Engineered Immune Cells to Treat Cancer. Clin Cancer Res. 2015 Sep 1;21(17):3957-68.
Gründer C et al. γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs. Blood 2012;120:5153-5162.
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