Human Vγ9Vδ2-T cells efficiently kill influenza virus-infected lung alveolar epithelial cells

Abstract

γδ-T cells play an indispensable role in host defense against different viruses, including influenza A virus. However, whether these cells have cytotoxic activity against influenza virus-infected lung alveolar epithelial cells and subsequently contribute to virus clearance remains unknown. Using influenza virus-infected A549 cells, human lung alveolar epithelial cells, we investigated the cytotoxic activity of aminobisphosphonate pamidronate (PAM)-expanded human Vγ9Vδ2-T cells and their underlying mechanisms. We found that PAM could selectively activate and expand human Vγ9Vδ2-T cells. PAM-expanded human Vγ9Vδ2-T cells efficiently killed influenza virus-infected lung alveolar epithelial cells and inhibited virus replication. The cytotoxic activity of PAM-expanded Vγ9Vδ2-T cells was dependent on cell-to-cell contact and required NKG2D activation. Perforin-granzyme B, tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas-Fas ligand (FasL) pathways were involved in their cytotoxicity. Our study suggests that targeting γδ-T cells by PAM can potentially offer an alternative option for the treatment of influenza virus.

Emerging role of γδ T cells in vaccine‐mediated protection from infectious diseases

“…Regarding influenza, several studies have shown that phosphoantigen or pamidronate-activated cd T cells are capable of inhibiting virus replication by killing influenza-infected macrophages 78 and/ or lung alveolar epithelial cells. 79 Phosphoantigenactivated cells also have non-cytolytic activities in response to pandemic H1N1, producing IFNc and expressing inflammatory chemokines. 80 Relatedly, it was also recently shown that Vc9Vd2 T cells can promote CD4 + T follicular helper cell differentiation, B-cell class switching and influenza virus-specific antibody production in an in vitro co-culture assay, 81 suggesting that these cells may provide both a direct cytotoxic and potential synergistic role in the adaptive immune response to influenza.…”

Lung‐resident γδ T cells and their roles in lung diseases

“…Human V γ 9V δ 2 T cells that are activated in vitro by aminobisphosphonate pamidronate efficiently kill influenza virus‐infected lung alveolar epithelial cells and inhibit virus replication in a cell‐to‐cell contact manner. The cytotoxic activity of V γ 9V δ 2 T cells requires NKG2D activation and involves perforin/granzyme B, TRAIL and FasL …”

Human γδ T‐cell receptor repertoire is shaped by influenza viruses, age and tissue compartmentalisation

“…In humans, γδ T cells respond to chronic viral infections, as suggested by their robust proliferative capacity during EBV reactivation, the upregulation of effector functions during HIV persistence, increased CD69 expression and expansion of δ1/δ3 T cells in kidney transplant patients with associated CMV latency . In addition, phosphoantigen‐expanded human γδ T cells upregulated IFN‐γ and γδ T cells killed cells infected with human H1N1 and H5N1 influenza viruses . Whether pre‐activation is a requirement for killing of influenza virus‐infected cells is unknown.…”

“…7 In addition, phosphoantigen-expanded human cd T cells upregulated IFN-c and cd T cells killed cells infected with human H1N1 and H5N1 influenza viruses. [8][9][10][11] Whether pre-activation is a requirement for killing of influenza virus-infected cells is unknown.…”