Extracellular vesicles from activated Vδ2 T cells inhibit viral replication and enhance adaptive antiviral immunity

Background: Vδ2 T cells are promising candidates for approaches of immunotherapy due to their unique pleiotropic functions; they were recently shown to enhance antiviral protection in hematopoietic stem cell transplantation (HSCT) recipients via innate effector activity and modulation of virus-specific adaptive T-cell response. Extracellular Vesicles (EVs) are key carriers of immunomodulatory signals and Vδ2-derived EVs (Vδ2-EVs) exhibit antitumor activity but their role in viral infection remain unclear. The aim of this study was to investigate the direct and immunomodulatory antiviral functions of Vδ2-EVs in healthy subjects and HSCT patients. Methods: The direct antiviral activity of Vδ2-EVs were tested in vitro using a model of Cytomegalovirus (CMV) replication. The immunomodulatory antiviral activities of Vδ2-EVs were evaluated in both healthy donors and HSCT recipients by functional immunological assays (cytokine release and proliferation capability of virus-specific T cells). Finally, their molecular cargo was characterized through miRNA sequencing. Results: Our findings reveal that Vδ2-EVs efficiently inhibit CMV replication, reducing the frequency of CMV-infected fibroblast cells. Moreover, Vδ2-EVs are taken up by myeloid cells and were able to activate antigen-presenting cells, leading to an increased frequency of CMV-specific T cells, as measured by IFN-γ production. Accordingly, Vδ2-EVs enhanced the proliferation of CMV-specific T-cell clones in HSCT pediatric recipients. Finally, the analysis of miRNA content in Vδ2-EVs highlighted the enrichment of miRNAs that target genes regulating critical antiviral response processes such as SOCS1. Conclusions: Altogether, this study provides new insights into the antiviral functions of Vδ2-EVs and underscores their translational therapeutic potential as modulators of antiviral immunity in immunocompromised settings.