The Role of gamma delta T Cells as a Line of Defense in Viral Infections after Allogeneic Stem Cell Transplantation: Opportunities and Challenges

In the complex interplay between inflammation and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-HSCT), viral reactivations are often observed and cause substantial morbidity and mortality. As toxicity after allo-HSCT within the context of viral reactivations is mainly driven by alpha beta T cells, we describe that by delaying alpha beta T cell reconstitution through defined transplantation techniques, we can harvest the full potential of early reconstituting gamma delta T cells to control viral reactivations. We summarize evidence of how the gamma delta T cell repertoire is shaped by CMV and EBV reactivations after allo-HSCT, and their potential role in controlling the most important, but not all, viral reactivations. As most gamma delta T cells recognize their targets in an MHC-independent manner, gamma delta T cells not only have the potential to control viral reactivations but also to impact the underlying hematological malignancies. We also highlight the recently re-discovered ability to recognize classical HLA-molecules through a gamma delta T cell receptor, which also surprisingly do not associate with GVHD. Finally, we discuss the therapeutic potential of gamma delta T cells and their receptors within and outside the context of allo-HSCT, as well as the opportunities and challenges for developers and for payers.