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γδ T-cells represent key players in the immune-surveillance after TCR alpha/beta (αβ)/CD19-depleted HLA-Haploidentical Stem Cell Transplantation (haplo-HSCT). Although encouraging data are available on the impact of Vδ2-targeting-therapy in improving HSCT-clinical outcomes, their role in providing antimicrobial immunity is largely unexplored. This study aimed to investigate the antiviral protective profile of Vδ2 T-cells in pediatric patients given this type of allograft. The characterization of γδ T-cells was performed by flow cytometry in haplo-HSCT-pediatric patients (n=26) in the donor graft and after 30, 60 and 120 days post-HSCT. The antiviral activity of Vδ2 T-cells was assessed on CMV-infected-fibroblasts and the CMV-specific αβ T-cell immunity was analyzed by flow cytometry. Early after HSCT, frequency of Vδ2 T-cells was significantly higher in patients who did not experience viral reactivation (No-VR) than in patients with CMV reactivation (CMV-R). Interestingly, this difference was already present in the grafts. Clustering analysis identified a protective subset of Vδ2 T-cells in No-VR patients, which expresses CD16, NKG2D, and CD107a and produces high levels of IFN-γ. This subset directly correlated with IL-15 and inversely with the CMV-DNA level. Stimulated Vδ2 T-cells inhibit CMV replication, acquired CD86/HLA-DR molecules, induced HLA-DR on monocytes, and improved the αβ CMV-specific T-cell response. Altogether, these results identify an antiviral protective profile displayed by Vδ2 T-cells early after HSCT, and define their ability to inhibit CMV replication, to induce antigen-presenting cell maturation and to improve αβ virus-specific T-cell response, opening a new application of Vδ2-targeting immunotherapy after HSCT, adding the antiviral to the antitumor potential., (Copyright © 2024 American Society of Hematology.)