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

Abstract

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 αβ T cells, we describe that by delaying αβ T cell reconstitution through defined transplantation techniques, we can harvest the full potential of early reconstituting γδ T cells to control viral reactivations. We summarize evidence of how the γδ 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 γδ T cells recognize their targets in an MHC-independent manner, γδ 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 γδ T cell receptor, which also surprisingly do not associate with GVHD. Finally, we discuss the therapeutic potential of γδ 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.

Phase I study of zoledronic acid combined with escalated doses of interleukine‐2 for early in vivo generation of Vγ9Vδ2 T‐cells after haploidentical stem cell transplant with posttransplant cyclophosphamide

“…19 In this context, the role of non-Vδ2 subsets in the immune response, particularly in anti-CMV antiviral activity, has been shown. [45][46][47][48] In the present study, an expansion of Vδ1 T-cells was indeed observed in the two patients with CMV reactivation. Interestingly, these data suggest a protective effect of the Vδ1 population on EBV viremia, although it is difficult to draw a firm conclusion on this point, since this study was not designed to address this specific issue.…”

“…Most published research evaluating the impact of γδ T‐cell reconstitution has primarily focused on recipients of ex vivo T‐cell‐depleted grafts, demonstrating a correlation between good γδ T‐cell reconstitution after HSCT and better outcomes, translating in improved PFS 18–20 and OS 18 with lower infection rates 19 . In this context, the role of non‐Vδ2 subsets in the immune response, particularly in anti‐CMV antiviral activity, has been shown 45–48 . In the present study, an expansion of Vδ1 T‐cells was indeed observed in the two patients with CMV reactivation.…”

Analysis of the Seasonal Fluctuation of γδ T Cells and Its Potential Relation with Vitamin D3

“…Even though a numerically small subset of peripheral blood T cells, γδ T cells fulfill important functions in the immune response to infection and stressed/transformed cells [10][11][12]. Because of their HLA-nonrestricted mode of action and potent cytotoxic activity, multiple approaches are currently under investigation to apply γδ T cells in immunotherapy of cancer and viral (re)infection [10][11][12]62,63]. The recent demonstration that it is safe to transfer γδ T cells expanded in vitro from healthy donors across HLA barriers into cancer patients has opened the way to apply off-the-shelf γδ T cell therapy to treat cancer patients [64].…”

AIM™ platform: A new immunotherapy approach for viral diseases

“…AIM ACT consist of ≥ 90% CD3 + /CD8 + and CD3 + /CD4 − CD8 − T cells, the latter being primarily gd T cells. Several recent reviews highlight the increasing interest in using gd T cells for cancer treatment and more recently for viral infections (23)(24)(25)(26). In our AIM ACT trials we have confirmed that E+E cells are well tolerated with no induced graft-vs-host disease (GVHD) or other grade 3-4 In the preclinical validation of NEXI003, the AIM platform consistently generated high quality cytotoxic T cells for HPV-associated cancer treatment.…”