Introduction: Vγ2Vδ2 T cells express a variety of cytotoxic NK and T cell surface receptors, enabling recognition of multiple stress molecules expressed during infection or cellular transformation. This diverse antigen recognition capacity supports the unique immunotherapeutic potential of γδ T cells. Vδ2 T cells can be selectively expanded through the application of aminobisphosphonate drugs, and adoptive transfer of expanded Vδ2 T cells has been well tolerated in clinical trials against various cancers. These trials have reported varying efficacies, which may be attributed to the high degree of inter-patient Vδ2 T cell heterogeneity. More potently inducing cytotoxic function may be a key to improving future Vδ2 T cell-based immunotherapies. We investigated mechanisms of target cell recognition by a variety of Vδ2 T cell surface receptors and explored protocols which may be enhance in vitro cytotoxicity.
Methods: Using a series of redirected LDH cytotoxicity assays, we evaluated mechanisms of target cell lysis by individual Vδ2 T cell surface receptors. In addition, we examined the impact of stimulation with combinations of cytokines during in vitro expansion on Vδ2 T cell mediated cytotoxicity.
Results: We found that Vδ2 T cells were capable of mediating direct lysis of target cells through NKG2D, CD16, CD3, and CD26. We found some evidence that NKG2D, CD16, CD3, CD26, 2B4, and DNAM-1 could contribute costimulatory activation signals to enhance lysis mediated through other Vδ2 T cell receptors. Finally, we observed certain cytokine combinations were capable of boosting Vδ2 mediated cytotoxicity.
Conclusion: We profiled Vδ2 T cell surface receptors capable of mediating direct lysis of target cells and identify factors capable of increasing this lysis. These findings may have key implications to improve upon Vδ2 T cell-based immunotherapies.