Antiviral potential of Vδ2 T cells in children given TCR αβ/CD19 cell-depleted HLA-haploidentical HSCT

γδ T cells represent key players in immune surveillance after T-cell receptor α/β (αβ)/CD19-depleted HLA-haploidentical hematopoietic 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 haplo-HSCT. The characterization of γδ T cells was performed in pediatric recipients (n = 26) in the donor graft and at 30, 60, and 120 days after haplo-HSCT. The antiviral activity of Vδ2 T cells and the cytomegalovirus (CMV)-specific αβ T-cell immunity was analyzed. Early after HSCT, Vδ2 T cells was significantly higher in patients who did not experience viral reactivation (No-VR) than in patients with CMV reactivation. Interestingly, this difference was already present in the grafts. Clustering analysis identified a protective subset of Vδ2 T cells in patients with No-VR, expressing CD16, NKG2D, and CD107a, and producing Th1 cytokines. This subset directly correlated with interleukin-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.